Heterocyclic compounds, pharmaceutical compositions containing them, and their use in therapy

ABSTRACT

The present invention relates to heterocyclic compounds of the formula (I) 
     
       
         
         
             
             
         
       
     
     or a physiologically tolerated salt thereof. 
     The present invention also relates to pharmaceutical compositions comprising such heterocyclic compounds, and the use of such heterocyclic compounds for therapeutic purposes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This claims the benefit of U.S. Provisional Patent Application No.61/152,822, filed on Feb. 16, 2009, the contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to heterocyclic compounds such as fusedtetrahydropyridines, pharmaceutical compositions comprising suchheterocyclic compounds, and the use of such heterocyclic compounds fortherapeutic purposes.

BACKGROUND OF THE INVENTION

Dysfunction of glutamatergic pathways has been implicated in a number ofdisease states in the human central nervous system (CNS) including butnot limited to schizophrenia, cognitive deficits, dementia, Parkinsondisease, Alzheimer disease and bipolar disorder. A large number ofstudies in animal models lend support to the NMDA hypofunctionhypothesis of schizophrenia.

NMDA receptor function can be modulated by altering the availability ofthe co-agonist glycine. This approach has the critical advantage ofmaintaining activity-dependent activation of the NMDA receptor becausean increase in the synaptic concentration of glycine will not produce anactivation of NMDA receptors in the absence of glutamate. Since synapticglutamate levels are tightly maintained by high affinity transportmechanisms, an increased activation of the glycine site will onlyenhance the NMDA component of activated synapses.

Two specific glycine transporters, GlyT1 and GlyT2 have been identifiedand shown to belong to the Na/Cl-dependent family of neurotransmittertransporters which includes taurine, gamma-aminobutyric acid (GABA),proline, monoamines and orphan transporters. GlyT1 and GlyT2 have beenisolated from different species and shown to have only 50% identity atthe amino acid level. They also have a different pattern of expressionin mammalian central nervous system, with GlyT2 being expressed inspinal cord, brainstem and cerebellum and GlyT1 present in these regionsas well as forebrain areas such as cortex, hippocampus, septum andthalamus. At the cellular level, GlyT2 has been reported to be expressedby glycinergic nerve endings in rat spinal cord whereas GlyT1 appears tobe preferentially expressed by glial cells. These expression studieshave led to the suggestion that GlyT2 is predominantly responsible forglycine uptake at glycinergic synapses whereas GlyT1 is involved inmonitoring glycine concentration in the vicinity of NMDA receptorexpressing synapses. Recent functional studies in rat have shown thatblockade of GlyT1 with the potent inhibitor(N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl])-sarcosine (NFPS)potentiates NMDA receptor activity and NMDA receptor-dependent long-termpotentiation in rat.

Molecular cloning has further revealed the existence of three variantsof GlyT1, termed GlyT-1a, GlyT-1b and GlyT-1c, each of which displays aunique distribution in the brain and peripheral tissues. The variantsarise by differential splicing and exon usage, and differ in theirN-terminal regions.

The physiological effects of GlyT1 in forebrain regions together withclinical reports showing the beneficial effects of GlyT1 inhibitorsarcosine in improving symptoms in schizophrenia patients suggest thatselective GlyT1 inhibitors represent a new class of antipsychotic drugs.

Glycine transporter inhibitors are already known in the art, forexample:

(see also Hashimoto K., Recent Patents on CNS Drug Discovery, 2006, 1,43-53; Harsing L. G. et al., Current Medicinal Chemistry, 2006, 13,1017-1044; Javitt D. C., Molecular Psychiatry (2004) 9, 984-997;Lindsley, C. W. et al., Current Topics in Medicinal Chemistry, 2006, 6,771-785; Lindsley C. W. et al., Current Topics in Medicinal Chemistry,2006, 6, 1883-1896).

It was one object of the present invention to provide further glycinetransporter inhibitors.

SUMMARY OF THE INVENTION

The present invention relates to heterocyclic compounds of the formula(I)

-   wherein-   A is a 5- or 6-membered heterocyclic ring;-   R is R¹—W-A¹-Q-Y-A²-X¹—;-   R¹ is hydrogen, alkyl, cycloalkylalkyl, halogenated alkyl,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl,    dialkylaminoalkyl, alkylcarbonylaminoalkyl,    alkyloxycarbonylaminoalkyl, alkylaminocarbonylaminoalkyl,    dialkylaminocarbonylaminoalkyl, alkylsulfonylaminoalkyl, (optionally    substituted arylalkyl)aminoalkyl, optionally substituted arylalkyl,    optionally substituted heterocyclylalkyl, cycloalkyl, alkylcarbonyl,    alkoxycarbonyl, halogenated alkoxycarbonyl, aryloxycarbonyl,    aminocarbonyl, alkylaminocarbonyl, (halogenated alkyl)aminocarbonyl,    arylaminocarbonyl, alkenyl, alkynyl, optionally substituted aryl,    hydroxy, alkoxy, halogenated alkoxy, hydroxyalkoxy, alkoxyalkoxy,    aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy,    alkylcarbonylaminoalkoxy, arylcarbonylaminoalkoxy,    alkoxycarbonylaminoalkoxy, arylalkoxy, alkylsulfonylaminoalkoxy,    (halogenated alkyl)sulfonylaminoalkoxy, arylsulfonylaminoalkoxy,    (arylalkyl)sulfonylaminoalkoxy, heterocyclylsulfonylaminoalkoxy,    heterocyclylalkoxy, aryloxy, heterocyclyloxy, alkylthio, halogenated    alkylthio, alkylamino, (halogenated alkyl)amino, dialkylamino,    di-(halogenated alkyl)amino, alkylcarbonylamino, (halogenated    alkyl)carbonylamino, arylcarbonylamino, alkylsulfonylamino,    (halogenated alkyl)sulfonylamino, arylsulfonylamino or optionally    substituted heterocyclyl;-   W is —NR⁸— or a bond;-   A¹ is optionally substituted alkylene or a bond;-   Q is —S(O)₂—, —C(O)— or a bond;-   Y is —NR⁹— or a bond;-   A² is optionally substituted alkylene, alkylene-CO—, —CO-alkylene,    alkylene-O-alkylene, alkylene-NR¹⁰-alkylene, optionally substituted    alkenylen, optionally substituted alkynylene, optionally substituted    arylene, optionally substituted heteroarylene or a bond;-   X¹ is —O—, —NR¹¹—, —S—, optionally substituted alkylene, optionally    substituted alkenylen, optionally substituted alkynylene or a bond,-   with the proviso that if Q is a bond, W is —NR⁸— or Y is —NR⁹—;-   R² is hydrogen, halogen, alkyl, halogenated alkyl, hydroxyalkyl,    —CN, alkenyl, alkynyl, optionally substituted aryl, hydroxy, alkoxy,    halogenated alkoxy, alkoxycarbonyl, alkenyloxy, arylalkoxy,    alkylcarbonyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl,    aminosulfonyl, amino, alkylamino, alkenylamino, nitro or optionally    substituted heterocyclyl, or two radicals R² together with the ring    atoms of A to which they are bound form an optionally substituted 5-    or 6-membered ring;-   R³ is hydrogen, halogen, alkyl or alkoxy, or two radicals R³    together with the carbon atom to which they are attached form a    carbonyl group;-   R⁴ is hydrogen, alkyl, halogenated alkyl, hydroxyalkyl, alkoxyalkyl,    aminoalkyl, CH₂CN, —CHO, alkylcarbonyl, (halogenated alkyl)carbonyl,    alkoxycarbonyl, arylcarbonyl, alkylaminocarbonyl, alkenyl,    —C(═NH)NH₂, —C(═NH)NHCN, alkylsulfonyl, arylsulfonyl, amino or    heterocyclyl;-   X² is —O—, —NR⁶—, —S—, >CR^(12a)R^(12b) or a bond;-   X³ is —O—, —NR⁷—, —S—, >CR^(13a)R^(13b) or a bond;-   R⁵ is optionally substituted aryl, optionally substituted cycloalkyl    or optionally substituted heterocyclyl;-   n is 0, 1, 2;-   R⁶ is hydrogen or alkyl;-   R⁷ is hydrogen or alkyl;-   R⁹ is hydrogen or alkyl;-   R⁹ is hydrogen, alkyl, cycloalkyl, aminoalkyl, optionally    substituted arylalkyl or heterocyclyl; or-   R⁹, R¹    -   together are alkylene; or-   R⁹ is alkylene that is bound to a carbon atom in A² and A² is    alkylene or to a carbon atom in X¹ and X¹ is alkylene;-   R¹⁰ is hydrogen, alkyl or alkylsulfonyl;-   R¹¹ is hydrogen or alkyl, or-   R⁹, R¹¹    -   together are alkylene,-   R^(12a) is hydrogen, optionally substituted alkyl, alkylaminoalkyl,    dialkylaminoalkyl, heterocyclylalkyl, optionally substituted aryl or    hydroxy;-   R^(12b) is hydrogen or alkyl, or-   R^(12a), R^(12b)    -   together are carbonyl or optionally substituted alkylene,        wherein one —CH₂— of alkylene may be replaced by an oxygen atom        or —NR¹⁴—;-   R^(13a) is hydrogen, optionally substituted alkyl, alkylaminoalkyl,    dialkylaminoalkyl, heterocyclylalkyl, optionally substituted aryl or    hydroxy;-   R^(13b) is hydrogen or alkyl, or-   R^(13a), R^(13b)    -   together are carbonyl or optionally substituted alkylene,        wherein one —CH₂— of alkylene may be replaced by an oxygen atom        or —NR¹⁵—;-   R¹⁴ is hydrogen or alkyl;-   R¹⁵ is hydrogen or alkyl; and-   or a physiologically tolerated salt thereof.

Thus, the present invention relates to heterocyclic compounds having theformula (Ia)

wherein A, R¹, W, A¹, Q, Y, A², X¹, R², R³, R⁴, X², X³, R⁵, n are asdefined herein.

Further, the present invention relates to heterocyclic compounds offormula (I) wherein R is —CN, i.e. heterocyclic compounds having theformula (Ib)

wherein A, R², R³, R⁴, X², X³, R⁵, n are as defined herein.

Thus, the term heterocyclic compound is used herein to denote inparticular tetrahydropyridines (n=1) fused to 5- or 6-memberedheterocyclic ring as well as homologous bicyclic compounds wherein n is0 or 2.

Said compounds of formula (I), i.e., the heterocyclic compounds offormula (I) and their physiologically tolerated acid addition salts, areglycine transporter inhibitors and thus useful as pharmaceuticals.

The present invention thus further relates to the compounds of formula(I) for use in therapy.

The present invention also relates to pharmaceutical compositions whichcomprise a carrier and a compound of formula (I).

In particular, said compounds, i.e., the heterocyclic compounds andtheir physiologically tolerated acid addition salts, are inhibitors ofthe glycine transporter GlyT1.

The present invention thus further relates to the compounds of formula(I) for use in inhibiting the glycine transporter.

The present invention also relates to the use of the compounds offormula (I) in the manufacture of a medicament for inhibiting theglycine transporter GlyT1 and corresponding methods of inhibiting theglycine transporter GlyT1.

Glycine transport inhibitors and in particular inhibitors of the glycinetransporter GlyT1 are known to be useful in treating a variety ofneurologic and psychiatric disorders.

The present invention thus further relates to the compounds of formula(I) for use in treating a neurologic or psychiatric disorder.

The present invention further relates to the compounds of formula (I)for use in treating pain.

The present invention also relates to the use of the compounds offormula (I) in the manufacture of a medicament for treating a neurologicor psychiatric disorder and corresponding methods of treating saiddisorders. The present invention also relates to the use of thecompounds of formula (I) in the manufacture of a medicament for treatingpain and corresponding methods of treating pain.

DETAILED DESCRIPTION

Provided that the heterocyclic compounds of the formula (I) of a givenconstitution may exist in different spatial arrangements, for example ifthey possess one or more centers of asymmetry, polysubstituted rings ordouble bonds, or as different tautomers, it is also possible to useenantiomeric mixtures, in particular racemates, diastereomeric mixturesand tautomeric mixtures, preferably, however, the respective essentiallypure enantiomers, diastereomers and tautomers of the compounds offormula (I) and/or of their salts.

According to one embodiment, an enantiomer of the heterocyclic compoundsof the present invention has the following formula:

wherein A, R, R², R³, X², X³, R⁴, R⁵ and n are as defined herein.

According to another embodiment, an enantiomer of the heterocycliccompounds of the present invention has the following formula:

wherein A, R, R², R³, X², X³, R⁴, R⁵ and n are as defined herein.

The physiologically tolerated salts of the heterocyclic compounds of theformula (I) are especially acid addition salts with physiologicallytolerated acids. Examples of suitable physiologically tolerated organicand inorganic acids are hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, C₁-C₄-alkylsulfonic acids, such as methanesulfonicacid, cycloaliphatic sulfonic acids, such as S-(+)-10-campher sulfonicacid, aromatic sulfonic acids, such as benzenesulfonic acid andtoluenesulfonic acid, di- and tricarboxylic acids and hydroxycarboxylicacids having 2 to 10 carbon atoms, such as oxalic acid, malonic acid,maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid,glycolic acid, adipic acid and benzoic acid. Other utilizable acids aredescribed, e.g., in Fortschritte der Arzneimittelforschung [Advances indrug research], Volume 10, pages 224 ff., Birkhäuser Verlag, Basel andStuttgart, 1966.

The present invention moreover relates to compounds of formula I asdefined herein, wherein at least one of the atoms has been replaced byits stable, non-radioactive isotope (e.g., hydrogen by deuterium, ¹²C by¹³C, ¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) and preferably wherein at least onehydrogen atom has been replaced by a deuterium atom.

Of course, such compounds contain more of the respective isotope thanthis naturally occurs and thus is anyway present in the compounds I.

Stable isotopes (e.g., deuterium, ¹³C, ¹⁵N, ¹⁸O) are nonradioactiveisotopes which contain one or more additional neutron than the normallyabundant isotope of the respective atom. Deuterated compounds have beenused in pharmaceutical research to investigate the in vivo metabolicfate of the compounds by evaluation of the mechanism of action andmetabolic pathway of the non deuterated parent compound (Blake et al. J.Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are importantin the design of safe, effective therapeutic drugs, either because thein vivo active compound administered to the patient or because themetabolites produced from the parent compound prove to be toxic orcarcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp.2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp.Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J.Physiol. Pharmacol., 77, 79-88 (1999).

Incorporation of a heavy atom particularly substitution of deuterium forhydrogen, can give rise to an isotope effect that could alter thepharmacokinetics of the drug. This effect is usually insignificant ifthe label is placed at a metabolically inert position of the molecule.

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These changes may influencethe fate of the drug at different steps along its passage through thebody. Absorption, distribution, metabolism or excretion can be changed.Absorption and distribution are processes that depend primarily on themolecular size and the lipophilicity of the substance. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction.

Drug metabolism can give rise to large isotopic effect if the breakingof a chemical bond to a deuterium atom is the rate limiting step in theprocess. While some of the physical properties of a stableisotope-labeled molecule are different from those of the unlabeled one,the chemical and biological properties are the same, with one importantexception: because of the increased mass of the heavy isotope, any bondinvolving the heavy isotope and another atom will be stronger than thesame bond between the light isotope and that atom. In any reaction inwhich the breaking of this bond is the rate limiting step, the reactionwill proceed slower for the molecule with the heavy isotope due to“kinetic isotope effect”. A reaction involving breaking a C-D bond canbe up to 700 percent slower than a similar reaction involving breaking aC—H bond. If the C-D bond is not involved in any of the steps leading tothe metabolite, there may not be any effect to alter the behavior of thedrug. If a deuterium is placed at a site involved in the metabolism of adrug, an isotope effect will be observed only if breaking of the C-Dbond is the rate limiting step. There is evidence to suggest thatwhenever cleavage of an aliphatic C—H bond occurs, usually by oxidationcatalyzed by a mixed-function oxidase, replacement of the hydrogen bydeuterium will lead to observable isotope effect. It is also importantto understand that the incorporation of deuterium at the site ofmetabolism slows its rate to the point where another metabolite producedby attack at a carbon atom not substituted by deuterium becomes themajor pathway a process called “metabolic switching”.

Deuterium tracers, such as deuterium-labeled drugs and doses, in somecases repeatedly, of thousands of milligrams of deuterated water, arealso used in healthy humans of all ages, including neonates and pregnantwomen, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control.Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989114: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al.Am. J. Obstet. Gynecol. 1981 139: 948). Thus, it is clear that anydeuterium released, for instance, during the metabolism of compounds ofthis invention poses no health risk.

The weight percentage of hydrogen in a mammal (approximately 9%) andnatural abundance of deuterium (approximately 0.015%) indicates that a70 kg human normally contains nearly a gram of deuterium. Furthermore,replacement of up to about 15% of normal hydrogen with deuterium hasbeen effected and maintained for a period of days to weeks in mammals,including rodents and dogs, with minimal observed adverse effects(Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson JF, Ann. New York Acad. Sci. 1960 84: 736; Czakja D M et al., Am. J.Physiol. 1961 201: 357). Higher deuterium concentrations, usually inexcess of 20%, can be toxic in animals. However, acute replacement of ashigh as 15%-23% of the hydrogen in humans' fluids with deuterium wasfound not to cause toxicity (Blagojevic N et al. in “Dosimetry &Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares Gand Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23: 251 (1997)).

Increasing the amount of deuterium present in a compound above itsnatural abundance is called enrichment or deuterium-enrichment. Examplesof the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71,75, 79, 84, 88, 92, 96, to about 100 mol %.

The hydrogens present on a particular organic compound have differentcapacities for exchange with deuterium. Certain hydrogen atoms areeasily exchangeable under physiological conditions and, if replaced bydeuterium atoms, it is expected that they will readily exchange forprotons after administration to a patient. Certain hydrogen atoms may beexchanged for deuterium atoms by the action of a deuteric acid such asD₂SO₄/D₂O. Alternatively, deuterium atoms may be incorporated in variouscombinations during the synthesis of compounds of the invention. Certainhydrogen atoms are not easily exchangeable for deuterium atoms. However,deuterium atoms at the remaining positions may be incorporated by theuse of deuterated starting materials or intermediates during theconstruction of compounds of the invention.

Deuterated and deuterium-enriched compounds of the invention can beprepared by using known methods described in the literature. Suchmethods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure. Relevant procedures and intermediates are disclosed,for instance in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996);Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B etal., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223,WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189;7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and USPatent Application Publication Nos. 20090137457; 20090131485;20090131363; 20090118238; 20090111840; 20090105338; 20090105307;20090105147; 20090093422; 20090088416; 20090082471, the methods arehereby incorporated by reference.

The organic moieties mentioned in the above definitions of the variablesare—like the term halogen—collective terms for individual listings ofthe individual group members. The prefix C_(n)—C_(m) indicates in eachcase the possible number of carbon atoms in the group.

Unless indicated otherwise, the term “substituted” means that a radicalis substituted with 1, 2 or 3, especially 1, substituent which are inparticular selected from the group consisting of halogen, C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, C₃-C₁₂-heterocyclyl-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl, C₁-C₄-alkenyl, OH, SH, CN,CF₃, O—CF₃, COOH, O—CH₂—COOH, C₁-C₆-alkoxy, C₁-C₆-alkylthio,C₃-C₇-cycloalkyl, COO—C₁-C₆-alkyl, CONH₂, CONH—C₁-C₆-alkyl,SO₂NH—C₁-C₆-alkyl, CON—(C₁-C₆-alkyl)₂, SO₂N—(C₁-C₆-alkyl)₂, NH₂,NH—C₁-C₆-alkyl, N—(C₁-C₆-alkyl)₂, NH—(C₁-C₄-alkyl-C₆-C₁₂-aryl),NH—CO—C₁-C₆-alkyl, NH—SO₂—C₁-C₆-alkyl, SO₂—C₁-C₆-alkyl, C₆-C₁₂-aryl,O—C₆-C₁₂-aryl, O—CH₂—C₆-C₁₂-aryl, CONH—C₆-C₁₂-aryl, SO₂NH—C₆-C₁₂-aryl,CONH—C₃-C₁₂-heterocyclyl, SO₂NH—C₃-C₁₂-heterocyclyl, SO₂—C₆-C₁₂ aryl,NH—SO₂—C₆-C₁₂-aryl, NH—CO—C₆-C₁₂-aryl, NH—SO₂—C₃-C₁₂-heterocyclyl,NH—CO—C₃-C₁₂-heterocyclyl and C₃-C₁₂-heterocyclyl, wherein aryl andheterocyclyl in turn may be unsubstituted or substituted with 1, 2 or 3substituents selected from the group consisting of halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

The term halogen denotes in each case fluorine, bromine, chlorine oriodine, in particular fluorine or chlorine.

C₁-C₄-Alkyl is a straight-chain or branched alkyl group having from 1 to4 carbon atoms. Examples of an alkyl group are methyl, C₂-C₄-alkyl suchas ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl ortert-butyl. C₁-C₂-Alkyl is methyl or ethyl, C₁-C₃-alkyl is additionallyn-propyl or isopropyl.

C₁-C₆-Alkyl is a straight-chain or branched alkyl group having from 1 to6 carbon atoms. Examples include methyl, C₂-C₄-alkyl as mentioned hereinand also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

Halogenated C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, wherein at least one, e.g. 1, 2, 3, 4 orall of the hydrogen atoms are replaced by 1, 2, 3, 4 or a correspondingnumber of identical or different halogen atoms, such as inhalogenomethyl, dihalogenomethyl, trihalogenomethyl,(R)-1-halogenoethyl, (S)-1-halogenoethyl, 2-halogenoethyl,1,1-dihalogenoethyl, 2,2-dihalogenoethyl, 2,2,2-trihalogenoethyl,(R)-1-halogenopropyl, (S)-1-halogenopropyl, 2-halogenopropyl,3-halogenopropyl, 1,1-dihalogenopropyl, 2,2-dihalogenopropyl,3,3-dihalogenopropyl, 3,3,3-trihalogenopropyl,(R)-2-halogeno-1-methylethyl, (S)-2-halogeno-1-methylethyl,(R)-2,2-dihalogeno-1-methylethyl, (S)-2,2-dihalogeno-1-methylethyl,(R)-1,2-dihalogeno-1-methylethyl, (S)-1,2-dihalogeno-1-methylethyl,(R)-2,2,2-trihalogeno-1-methylethyl,(S)-2,2,2-trihalogeno-1-methylethyl, 2-halogeno-1-(halogenomethyl)ethyl,1-(dihalogenomethyl)-2,2-dihalogenoethyl, (R)-1-halogenobutyl,(S)-1-halogenobutyl, 2-halogenobutyl, 3-halogenobutyl, 4-halogenobutyl,1,1-dihalogenobutyl, 2,2-dihalogenobutyl, 3,3-dihalogenobutyl,4,4-dihalogenobutyl, 4,4,4-trihalogenobutyl, etc. Particular examplesinclude the fluorinated C₁-C₄ alkyl groups as defined, such astrifluoromethyl.

C₆-C₁₂-Aryl-C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by C₆-C₁₂-aryl, such as in benzyl.

Hydroxy-C₁-C₄-alkyl is a straight-chain or branched alkyl group having 1to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or2 carbon atoms, wherein one or two hydrogen atoms are replaced by one ortwo hydroxyl groups, such as in hydroxymethyl, (R)-1-hydroxyethyl,(S)-1-hydroxyethyl, 2-hydroxyethyl, (R)-1-hydroxypropyl,(S)-1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,(R)-2-hydroxy-1-methylethyl, (S)-2-hydroxy-1-methylethyl,2-hydroxy-1-(hydroxymethyl)ethyl, (R)-1-hydroxybutyl,(S)-1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl.

C₁-C₆-Alkoxy-C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms arereplaced by one or two alkoxy groups having 1 to 6, preferably 1 to 4,in particular 1 or 2 carbon atoms, such as in methoxymethyl,(R)-1-methoxyethyl, (S)-1-methoxyethyl, 2-methoxyethyl,(R)-1-methoxypropyl, (S)-1-methoxypropyl, 2-methoxypropyl,3-methoxypropyl, (R)-2-methoxy-1-methylethyl,(S)-2-methoxy-1-methylethyl, 2-methoxy-1-(methoxymethyl)ethyl,(R)-1-methoxybutyl, (S)-1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl,4-methoxybutyl, ethoxymethyl, (R)-1-ethoxyethyl, (S)-1-ethoxyethyl,2-ethoxyethyl, (R)-1-ethoxypropyl, (S)-1-ethoxypropyl, 2-ethoxypropyl,3-ethoxypropyl, (R)-2-ethoxy-1-methylethyl, (S)-2-ethoxy-1-methylethyl,2-ethoxy-1-(ethoxymethyl)ethyl, (R)-1-ethoxybutyl, (S)-1-ethoxybutyl,2-ethoxybutyl, 3-ethoxybutyl, 4-ethoxybutyl.

Amino-C₁-C₄-alkyl is a straight-chain or branched alkyl group having 1to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or2 carbon atoms, in particular 1 or two carbon atoms, wherein onehydrogen atom is replaced by an amino group, such as in amino methyl,2-aminoethyl.

C₁-C₆-Alkylamino-C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by a C₁-C₆-alkylamino group, inparticular by a C₁-C₄-alkylamino group, such as in methylaminomethyl,ethylaminomethyl, n-propylaminomethyl, iso-propylaminomethyl,n-butylaminomethyl, 2-butylaminomethyl, iso-butylaminomethyl ortert-butylaminomethyl.

Di-C₁-C₆-Alkylamino-C₁-C₄-alkyl is a straight-chain or branched alkylgroup having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by a di-C₁-C₆-Alkylamino group, inparticular by a di-C₁-C₄-alkylamino group, such as indimethylaminomethyl.

C₁-C₆-Alkylcarbonylamino-C₁-C₄-alkyl is a straight-chain or branchedalkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms,more preferably 1 or 2 carbon atoms, in particular 1 or two carbonatoms, wherein one hydrogen atom is replaced by aC₁-C₆-alkylcarbonylamino group, in particular by aC₁-C₄-alkylcarbonylamino group, such as in methylcarbonylaminomethyl,ethylcarbonylaminomethyl, n-propylcarbonylaminomethyl,iso-propylcarbonylaminomethyl, n-butylcarbonylaminomethyl,2-butylcarbonylaminomethyl, iso-butylcarbonylaminomethyl ortert-butylcarbonylaminomethyl.

C₁-C₆-Alkylaminocarbonylamino-C₁-C₄-alkyl is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 ortwo carbon atoms, wherein one hydrogen atom is replaced by aC₁-C₆-alkylaminocarbonylamino group, in particular by aC₁-C₄-alkylaminocarbonylamino group, such as inmethylaminocarbonylaminomethyl, ethylaminocarbonylaminomethyl,n-propylaminocarbonylaminomethyl, iso-propylaminocarbonylaminomethyl,n-butylaminocarbonylaminomethyl, 2-butylaminocarbonylaminomethyl,iso-butylaminocarbonylaminomethyl or tert-butylaminocarbonylaminomethyl.

Di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 ortwo carbon atoms, wherein one hydrogen atom is replaced by adi-C₁-C₆-alkylaminocarbonylamino group, in particular by adi-C₁-C₄-alkylaminocarbonylamino group, such as indimethylaminocarbonylaminomethyl, dimethylaminocarbonylaminoethyl,dimethylaminocarbonylaminon-propyl.

C₁-C₆-Alkylsulfonylamino-C₁-C₄-alkyl is a straight-chain or branchedalkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms,more preferably 1 or 2 carbon atoms, in particular 1 or two carbonatoms, wherein one hydrogen atom is replaced by aC₁-C₆-alkylsulfonylamino group, in particular by aC₁-C₄-alkylsulfonylamino group, such as in methylsulfonylaminomethyl,ethylsulfonylaminomethyl, n-propylsulfonylaminomethyl,iso-propylsulfonylaminomethyl, n-butylsulfonylaminomethyl,2-butylsulfonylaminomethyl, iso-butylsulfonylaminomethyl ortert-butylsulfonylaminomethyl.

(C₆-C₁₂-Aryl-C₁-C₆-alkyl)amino-C₁-C₄ alkyl is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 ortwo carbon atoms, wherein one hydrogen atom is replaced by a(C₆-C₁₂-aryl-C₁-C₆-alkyl)amino group, in particular a(C₆-C₁₂-aryl-C₁-C₂-alkyl)amino group, such as in benzylaminomethyl.

C₃-C₁₂-Heterocyclyl-C₁-C₄-alkyl is a straight-chain or branched alkylgroup having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by C₃-C₁₂-heterocyclyl, such as inN-pyrrolidinylmethyl, N-piperidinylmethyl, N-morpholinylmethyl.

C₃-C₁₂-Cycloalkyl is a cycloaliphatic radical having from 3 to 12 carbonatoms. In particular, 3 to 6 carbon atoms form the cyclic structure,such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclicstructure may be unsubstituted or may carry 1, 2, 3 or 4 C₁-C₄ alkylradicals, preferably one or more methyl radicals.

Carbonyl is >C═O.

C₁-C₆-Alkylcarbonyl is a radical of the formula R—C(O)—, wherein R is analkyl radical having from 1 to 6, preferably from 1 to 4, in particular1 or 2 carbon atoms as defined herein. Examples include acetyl,propionyl, n-butyryl, 2-methylpropionyl, pivaloyl.

Halogenated C₁-C₆-alkylcarbonyl is C₁-C₆-alkylcarbonyl as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms. Examples include fluoromethylcarbonyl,difluoromethylcarbonyl, trifluoromethylcarbonyl. Further examples are1,1,1-trifluoroeth-2-ylcarbonyl, 1,1,1-trifluoroprop-3-ylcarbonyl.

C₆-C₁₂-Arylcarbonyl is a radical of the formula R—C(O)—, wherein R is anaryl radical having from 6 to 12 carbon atoms as defined herein.Examples include benzoyl.

C₁-C₆-Alkoxycarbonyl is a radical of the formula R—O—C(O)—, wherein R isan alkyl radical having from 1 to 6, preferably from 1 to 4, inparticular 1 or 2 carbon atoms as defined herein. Examples includemethoxycarbonyl and tert-butyloxycarbonyl.

Halogenated C₁-C₆-alkoxycarbonyl is a C₁-C₆-alkoxycarbonyl as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms.

C₆-C₁₂-Aryloxycarbonyl is a radical of the formula R—O—C(O)—, wherein Ris an aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenoxycarbonyl.

Cyano is —C≡N.

Aminocarbonyl is NH₂C(O)—.

C₁-C₆-Alkylaminocarbonyl is a radical of the formula R—NH—C(O)—, whereinR is an alkyl radical having from 1 to 6, preferably from 1 to 4, inparticular 1 or 2 carbon atoms as defined herein. Examples includemethylaminocarbonyl.

(Halogenated C₁-C₄-alkyl)aminocarbonyl is a C₁-C₄-alkylaminocarbonyl asdefined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number ofidentical or different hydrogen atoms.

C₆-C₁₂-Arylaminocarbonyl is a radical of the formula R—NH—C(O)—, whereinR is an aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenylaminocarbonyl.

C₂-C₆-Alkenyl is a singly unsaturated hydrocarbon radical having 2, 3,4, 5 or 6 carbon atoms, e.g. vinyl, allyl (2-propen-1-yl),1-propen-1-yl, 2-propen-2-yl, methallyl(2-methylprop-2-en-1-yl) and thelike. C₃-C₅-Alkenyl is, in particular, allyl, 1-methylprop-2-en-1-yl,2-buten-1-yl, 3-buten-1-yl, methallyl, 2-penten-1-yl, 3-penten-1-yl,4-penten-1-yl, 1-methylbut-2-en-1-yl or 2-ethylprop-2-en-1-yl.

C₂-C₆-Alkynyl is a singly unsaturated hydrocarbon radical having 2, 3,4, 5 or 6 carbon atoms, e.g. ethynyl, 2-propyn-1-yl, 1-propyn-1-yl,2-propyn-2-yl and the like. C₃-C₅-Alkynyl is, in particular,2-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl,4-pentyn-1-yl.

C₁-C₄-Alkylene is straight-chain or branched alkylene group having from1 to 4 carbon atoms. Examples include methylene and ethylene. A furtherexample is propylene.

C₂-C₄-Alkenylene is straight-chain or branched alkenylene group havingfrom 2 to 4 carbon atoms.

C₂-C₄-Alkynylene is straight-chain or branched alkynylene group havingfrom 2 to 4 carbon atoms. Examples include propynylene.

C₆-C₁₂-Aryl is a 6- to 12-membered, in particular 6- to 10-membered,aromatic cyclic radical. Examples include phenyl and naphthyl.

C₃-C₁₂-Arylene is an aryl diradical. Examples include phen-1,4-ylene andphen-1,3-ylene.

Hydroxy is —OH.

C₁-C₆-Alkoxy is a radical of the formula R—O—, wherein R is astraight-chain or branched alkyl group having from 1 to 6, in particular1 to 4 carbon atoms. Examples include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, 2-butoxy, iso-butoxy (2-methylpropoxy),tert.-butoxy pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy,2,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, 1-methylpentyloxy, 2-methylpentyloxy,3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutyloxy,1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,2-dimethylbutyloxy,2,3-dimethylbutyloxy, 3,3-dimethylbutyloxy, 1-ethylbutyloxy,2-ethylbutyloxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy,1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy.

Halogenated C₁-C₆-alkoxy is a straight-chain or branched alkoxy grouphaving from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbonatoms, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms, such as in halogenomethoxy,dihalogenomethoxy, trihalogenomethoxy, (R)-1-halogenoethoxy,(S)-1-halogenoethoxy, 2-halogenoethoxy, 1,1-dihalogenoethoxy,2,2-dihalogenoethoxy, 2,2,2-trihalogenoethoxy, (R)-1-halogenopropoxy,(S)-1-halogenopropoxy, 2-halogenopropoxy, 3-halogenopropoxy,1,1-dihalogenopropoxy, 2,2-dihalogenopropoxy, 3,3-dihalogenopropoxy,3,3,3-trihalogenopropoxy, (R)-2-halogeno-1-methylethoxy,(S)-2-halogeno-1-methylethoxy, (R)-2,2-dihalogeno-1-methylethoxy,(S)-2,2-dihalogeno-1-methylethoxy, (R)-1,2-dihalogeno-1-methylethoxy,(S)-1,2-dihalogeno-1-methylethoxy, (R)-2,2,2-trihalogeno-1-methylethoxy,(S)-2,2,2-trihalogeno-1-methylethoxy,2-halogeno-1-(halogenomethyl)ethoxy,1-(dihalogenomethyl)-2,2-dihalogenoethoxy, (R)-1-halogenobutoxy,(S)-1-halogenobutoxy, 2-halogenobutoxy, 3-halogenobutoxy,4-halogenobutoxy, 1,1-dihalogenobutoxy, 2,2-dihalogenobutoxy,3,3-dihalogenobutoxy, 4,4-dihalogenobutoxy, 4,4,4-trihalogenobutoxy,etc. Particular examples include the fluorinated C₁-C₄ alkoxy groups asdefined, such as trifluoromethoxy.

C₁-C₆-Hydroxyalkoxy is an alkoxy radical having from 1 to 6, preferablyfrom 1 to 4 carbon atoms as defined herein, wherein one or two hydrogenatoms are replaced by hydroxy. Examples include 2-hydroxyethoxy,3-hydroxypropoxy, 2-hydroxypropoxy, 1-methyl-2-hydroxyethoxy and thelike.

C₁-C₆-Alkoxy-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4 carbonatoms, preferably 1 or 2 carbon atoms as defined herein, wherein one ortwo hydrogen atoms are replaced by one or two alkoxy radicals havingfrom 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.Examples include methoxymethoxy, 2-methoxyethoxy, 1-methoxyethoxy,3-methoxypropoxy, 2-methoxypropoxy, 1-methyl-1-methoxyethoxy,ethoxymethoxy, 2-ethoxyethoxy, 1-ethoxyethoxy, 3-ethoxypropoxy,2-ethoxypropoxy, 1-methyl-1-ethoxyethoxy and the like.

Amino-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4, preferably 1or 2 carbon atoms as defined herein, wherein one hydrogen atom isreplaced by an amino group. Examples include 2-aminoethoxy.

C₁-C₆-Alkylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4,preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogenatom is replaced by an alkylamino group having from 1 to 6, preferablyfrom 1 to 4 carbon atoms as defined herein. Examples includemethylaminomethoxy, ethylaminomethoxy, n-propylaminomethoxy,iso-propylaminomethoxy, n-butylaminomethoxy, 2-butylaminomethoxy,iso-butylaminomethoxy, tert-butylaminomethoxy, 2-(methylamino)ethoxy,2-(ethylamino)ethoxy, 2-(n-propylamino)ethoxy,2-(iso-propylamino)ethoxy, 2-(n-butylamino)ethoxy,2-(2-butylamino)ethoxy, 2-(iso-butylamino)ethoxy,2-(tert-butylamino)ethoxy.

Di-C₁-C₆-alkylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1 to4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a dialkylamino group having from 1 to 6,preferably from 1 to 4 carbon atoms as defined herein. Examples includedimethylaminomethoxy, diethylaminomethoxy, N-methyl-N-ethylamino)ethoxy,2-(dimethylamino)ethoxy, 2-(diethylamino)ethoxy,2-(N-methyl-N-ethylamino)ethoxy.

C₁-C₆-Alkylcarbonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by an alkylcarbonylamino group wherein thealkyl group has from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methylcarbonylaminomethoxy,ethylcarbonylaminomethoxy, n-propylcarbonylaminomethoxy,iso-propylcarbonylaminomethoxy, n-butylcarbonylaminomethoxy,2-butylcarbonylaminomethoxy, iso-butylcarbonylaminomethoxy,tert-butylcarbonylaminomethoxy, 2-(methylcarbonylamino)ethoxy,2-(ethylcarbonylamino)ethoxy, 2-(n-propylcarbonylamino)ethoxy,2-(iso-propylcarbonylamino)ethoxy, 2-(n-butylcarbonylamino)ethoxy,2-(2-butylcarbonylamino)ethoxy, 2-(iso-butylcarbonylamino)ethoxy,2-(tert-butylcarbonylamino)ethoxy.

C₆-C₁₂-Arylcarbonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a C₆-C₁₂-arylcarbonylamino group as definedherein. Examples include 2-(benzoylamino)ethoxy.

C₁-C₆-Alkoxycarbonylamino-C₁-C₄-alkoxy is an alkoxy radical having from1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by an alkoxycarbonylamino group wherein thealkoxy group has from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methoxycarbonylaminomethoxy,ethoxycarbonylaminomethoxy, n-propoxycarbonylaminomethoxy,iso-propoxycarbonylaminomethoxy, n-butoxycarbonylaminomethoxy,2-butoxycarbonylaminomethoxy, iso-butoxycarbonylaminomethoxy,tert-butoxycarbonylaminomethoxy, 2-(methoxycarbonylamino)ethoxy,2-(ethoxycarbonylamino)ethoxy, 2-(n-propoxycarbonylamino)ethoxy,2-(iso-propoxycarbonylamino)ethoxy, 2-(n-butoxycarbonylamino)ethoxy,2-(2-butoxycarbonylamino)ethoxy, 2-(iso-butoxycarbonylamino)ethoxy,2-(tert-butoxycarbonylamino)ethoxy.

C₂-C₆-Alkenyloxy is a radical of the formula R—O—, wherein R is astraight-chain or branched alkenyl group having from 2 to 6, inparticular 2 to 4 carbon atoms. Examples include vinyloxy, allyloxy(2-propen-1-yloxy), 1-propen-1-yloxy, 2-propen-2-yloxy, methallyloxy(2-methylprop-2-en-1-yloxy) and the like. C₃-C₅-Alkenyloxy is, inparticular, allyloxy, 1-methylprop-2-en-1-yloxy, 2-buten-1-yloxy,3-buten-1-yloxy, methallyloxy, 2-penten-1-yloxy, 3-penten-1-yloxy,4-penten-1-yloxy, 1-methylbut-2-en-1-yloxy or 2-ethylprop-2-en-1-yloxy.

C₆-C₁₂-Aryl-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4,preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogenatom is replaced by a C₆-C₁₂-aryl group as defined herein. Examplesinclude benzyloxy.

C₁-C₆-Alkylsulfonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by an alkylsulfonylamino group having from 1to 6, preferably from 1 to 4 carbon atoms as defined herein. Examplesinclude 2-(methylsulfonylamino)ethoxy, 2-(ethylsulfonylamino)ethoxy,2-[(2-methylpropyl)sulfonylamino]ethoxy.

(Halogenated C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy is an alkoxy radicalhaving from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,wherein one hydrogen atom is replaced by an alkylsulfonylamino grouphaving from 1 to 6, preferably from 1 to 4 carbon atoms as definedherein, wherein the alkyl group is halogenated. Examples include2-(trifluoromethylsulfonylamino)ethoxy.

C₆-C₁₂-Arylsulfonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a C₆-C₁₂-arylsulfonylamino group as definedherein. Examples include 2-(phenylsulfonylamino)ethoxy,2-(naphthylsulfonylamino)ethoxy.

(C₆-C₁₂-Aryl-C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy is an alkoxy radicalhaving from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,wherein one hydrogen atom is replaced by a(C₆-C₁₂-aryl-C₁-C₆-alkyl)sulfonylamino group, preferably by a(C₆-C₁₂-aryl-C₁-C₂-alkyl)sulfonylamino group. Examples include2-(benzylsulfonylamino)ethoxy.

C₃-C₁₂-Heterocyclylsulfonylamino-C₁-C₄-alkoxy is an alkoxy radicalhaving from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,wherein one hydrogen atom is replaced by aC₃-C₁₂-heterocyclylsulfonylamino group as defined herein. Examplesinclude 2-(pyridin-3-yl-sulfonylamino)ethoxy.

C₃-C₁₂-Heterocyclyl-C₁-C₄-alkoxy is an alkoxy radical having from 1 to4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a C₃-C₁₂-heterocyclyl group as definedherein. Examples include 2-(N-pyrrolidinyl)ethoxy,2-(N-morpholinyl)ethoxy and 2-(N-imidazolyl)ethoxy.

C₁-C₂-Alkylenedioxo is a radical of the formula —O—R—O—, wherein R is astraight-chain or branched alkylene group having from 1 or 2 carbonatoms as defined herein. Examples include methylenedioxo.

C₆-C₁₂-Aryloxy is a radical of the formula R—O—, wherein R is an arylgroup having from 6 to 12, in particular 6 carbon atoms as definedherein. Examples include phenoxy.

C₃-C₁₂-Heterocyclyloxy is a radical of the formula R—O—, wherein R is aC₃-C₁₂-heterocyclyl group having from 3 to 12, in particular from 3 to 7carbon atoms as defined herein. Examples include pyridin-2-yloxy.

C₁-C₆-Alkylthio is a radical of the formula R—S—, wherein R is an alkylradical having from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methylthio, ethylthio, propylthio,butylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio,3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio,1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio,2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio,1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio,2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio,1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio,1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropyl and1-ethyl-2-methylpropyl.

Halogenated C₁-C₆-alkylthio is a radical of the formula R—S—, wherein Ris a halogenated alkyl radical having from 1 to 6, preferably from 1 to4 carbon atoms as defined herein. Examples include halogenomethylthio,dihalogenomethylthio, trihalogenomethylthio, (R)-1-halogenoethylthio,(S)-1-halogenoethylthio, 2-halogenoethylthio, 1,1-dihalogenoethylthio,2,2-dihalogenoethylthio, 2,2,2-trihalogenoethylthio,(R)-1-halogenopropylthio, (S)-1-halogenopropylthio,2-halogenopropylthio, 3-halogenopropylthio, 1,1-dihalogenopropylthio,2,2-dihalogenopropylthio, 3,3-dihalogenopropylthio,3,3,3-trihalogenopropylthio, (R)-2-halogeno-1-methylethylthio,(S)-2-halogeno-1-methylethylthio, (R)-2,2-dihalogeno-1-methylethylthio,(S)-2,2-dihalogeno-1-methylethylthio,(R)-1,2-dihalogeno-1-methylethylthio,(S)-1,2-dihalogeno-1-methylethylthio,(R)-2,2,2-trihalogeno-1-methylethylthio,(S)-2,2,2-trihalogeno-1-methylethylthio,2-halogeno-1-(halogenomethyl)ethylthio,1-(dihalogenomethyl)-2,2-dihalogenoethylthio, (R)-1-halogenobutylthio,(S)-1-halogenobutylthio, 2-halogenobutylthio, 3-halogenobutylthio,4-halogenobutylthio, 1,1-dihalogenobutylthio, 2,2-dihalogenobutylthio,3,3-dihalogenobutylthio, 4,4-dihalogenobutylthio,4,4,4-trihalogenobutylthio, etc. Particular examples include thefluorinated C₁-C₄alkylthio groups as defined, such astrifluoromethylthio.

C₁-C₆-Alkylsulfinyl is a radical of the formula R—S(O)—, wherein R is analkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methylsulfinyl, ethylsulfinyl,propylsulfinyl, butylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl,2-methylbutylsulfinyl, 3-methylbutylsulfinyl,2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl,1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl,1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl,4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl,1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl,2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl,3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl,1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

C₁-C₆-Alkylsulfonyl is a radical of the formula R—S(O)₂—, wherein R isan alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atomsas defined herein. Examples include methylsulfonyl, ethylsulfonyl,propylsulfonyl, butylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl,2-methylbutylsulfonyl, 3-methylbutylsulfonyl,2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl,1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl,1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl,4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl,1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl,2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl,3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl,1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

(Halogenated C₁-C₆-alkyl)sulfonyl is a C₁-C₆-alkylsulfonyl as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms.

C₆-C₁₂-Arylsulfonyl is a radical of the formula R—S(O)₂—, wherein R isan aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenylsulfonyl.

(C₆-C₁₂-Aryl-C₁-C₄-alkyl)sulfonyl is a radical of the formula R—S(O)₂—,wherein R is a C₆-C₁₂-aryl-C₁-C₄-alkyl radical, in particular aC₆-C₁₂-aryl-C₁-C₂-alkyl radical as defined herein. Examples includebenzylsulfonyl.

C₃-C₁₂-Heterocyclylsulfonyl is a radical of the formula R—S(O)₂—,wherein R is C₃-C₁₂-heterocyclyl as defined herein.

Aminosulfonyl is NH₂—S(O)₂—.

C₁-C₆-Alkylaminosulfonyl is a radical of the formula R—NH—S(O)₂— whereinR is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbonatoms as defined herein. Examples include methylaminosulfonyl,ethylaminosulfonyl, n-propylaminosulfonyl, iso-propylaminosulfonyl,n-butylaminosulfonyl, 2-butylaminosulfonyl, iso-butylaminosulfonyl,tert-butylaminosulfonyl.

Di-C₁-C₆-alkylaminosulfonyl is a radical of the formula RR′N—S(O)₂—wherein R and R′ are independently of each other an alkyl radical havingfrom 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.Examples include dimethylaminosulfonyl, diethylaminosulfonyl,N-methyl-N-ethylaminosulfonyl.

C₆-C₁₂-Arylaminosulfonyl is a radical of the formula R—NH—S(O)₂— whereinR is an aryl radical having from 6 to 12, preferably 6 carbon atoms asdefined herein.

Amino is NH₂.

C₁-C₆-Alkylamino is a radical of the formula R—NH— wherein R is an alkylradical having from 1 to 6, in particular from 1 to 4 carbon atoms asdefined herein. Examples include methylamino, ethylamino, n-propylamino,iso-propylamino, n-butylamino, 2-butylamino, iso-butylamino,tert-butylamino.

(Halogenated C₁-C₆-alkyl)amino is a C₁-C₆-alkylamino as defined herein,wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms arereplaced by 1, 2, 3, 4 or a corresponding number of identical ordifferent halogen atoms.

Di-C₁-C₆-alkylamino is a radical of the formula RR′N— wherein R and R′are independently of each other an alkyl radical having from 1 to 6, inparticular from 1 to 4 carbon atoms as defined herein. Examples includedimethylamino, diethylamino, N-methyl-N-ethylamino. Di-(halogenatedC₁-C₆-alkyl)amino is a di-C₁-C₆-alkylamino as defined herein, wherein atleast one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by1, 2, 3, 4 or a corresponding number of identical or different halogenatoms.

C₁-C₆-Alkylcarbonylamino is a radical of the formula R—C(O)—NH—, whereinR is an alkyl radical having from 1 to 6, in particular from 1 to 4carbon atoms as defined herein. Examples include acetamido(methylcarbonylamino), propionamido, n-butyramido, 2-methylpropionamido(isopropylcarbonylamino), 2,2-dimethylpropionamido and the like.

(Halogenated C₁-C₆-alkyl)carbonylamino is a C₁-C₆-alkylcarbonylamino asdefined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number ofidentical or different halogen atoms.

C₆-C₁₂-Arylcarbonylamino is a radical of the formula R—C(O)—NH—, whereinR is an aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenylcarbonylamino.

C₂-C₆-Alkenylamino is a radical of the formula R—NH—, wherein R is astraight-chain or branched alkenyl group having from 2 to 6, inparticular 2 to 4 carbon atoms. Examples include vinylamino, allylamino(2-propen-1-ylamino), 1-propen-1-ylamino, 2-propen-2-ylamino,methallylamino (2-methylprop-2-en-1-ylamino) and the like.C₃-C₅-Alkenylamino is, in particular, allylamino,1-methylprop-2-en-1-ylamino, 2-buten-1-ylamino, 3-buten-1-ylamino,methallylamino, 2-penten-1-ylamino, 3-penten-1-ylamino,4-penten-1-ylamino, 1-methylbut-2-en-1-ylamino or2-ethylprop-2-en-1-ylamino.

C₁-C₆-Alkylsulfonylamino is a radical of the formula R—S(O)₂—NH—,wherein R is an alkyl radical having from 1 to 6, in particular from 1to 4 carbon atoms as defined herein. Examples includemethylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino,iso-propylsulfonylamino, n-butylsulfonylamino, 2-butylsulfonylamino,iso-butylsulfonylamino, tert-butylsulfonylamino.

(Halogenated C₁-C₆ alkyl)sulfonylamino is a C₁-C₆-alkylsulfonylamino asdefined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number ofidentical or different halogen atoms.

C₆-C₁₂-Arylsulfonylamino is a radical of the formula R—S(O)₂—NH—,wherein R is an aryl radical having from 6 to 12 carbon atoms as definedherein. Examples include phenylsulfonylamino.

Nitro is —NO₂.

C₃-C₁₂-Heterocyclyl is a 3- to 12-membered heterocyclic radicalincluding a saturated heterocyclic radical, which generally has 3, 4, 5,6, or 7 ring forming atoms (ring members), an unsaturated non-aromaticheterocyclic radical, which generally has 5, 6 or 7 ring forming atoms,and a heteroaromatic radical (hetaryl), which generally has 5, 6 or 7ring forming atoms. The heterocyclic radicals may be bound via a carbonatom (C-bound) or a nitrogen atom (N-bound). Preferred heterocyclicradicals comprise 1 nitrogen atom as ring member atom and optionally 1,2 or 3 further heteroatoms as ring members, which are selected,independently of each other from O, S and N. Likewise preferredheterocyclic radicals comprise 1 heteroatom as ring member, which isselected from O, S and N, and optionally 1, 2 or 3 further nitrogenatoms as ring members.

Examples of C₃-C₁₂-heterocyclyl include:

C- or N-bound 3-4-membered, saturated rings, such as2-oxiranyl, 2-oxetanyl, 3-oxetanyl, 2-aziridinyl, 3-thiethanyl,1-azetidinyl, 2-azetidinyl, 3-azetidinyl;C-bound, 5-membered, saturated rings, such astetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl,tetrahydropyrazol-3-yl, tetrahydro-pyrazol-4-yl,tetrahydroisoxazol-3-yl, tetrahydroisoxazol-4-yl,tetrahydroisoxazol-5-yl, 1,2-oxathiolan-3-yl, 1,2-oxathiolan-4-yl,1,2-oxathiolan-5-yl, tetrahydroisothiazol-3-yl,tetrahydroisothiazol-4-yl, tetrahydroisothiazol-5-yl,1,2-dithiolan-3-yl, 1,2-dithiolan-4-yl, tetrahydroimidazol-2-yl,tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl, tetrahydrooxazol-4-yl,tetrahydrooxazol-5-yl, tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl,tetrahydrothiazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl,1,3-oxathiolan-2-yl, 1,3-oxathiolan-4-yl, 1,3-oxathiolan-5-yl,1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, 1,3,2-dioxathiolan-4-yl;C-bound, 6-membered, saturated rings, such astetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl,tetrahydrothiopyran-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl,1,3-dioxan-5-yl, 1,4-dioxan-2-yl, 1,3-dithian-2-yl, 1,3-dithian-4-yl,1,3-dithian-5-yl, 1,4-dithian-2-yl, 1,3-oxathian-2-yl,1,3-oxathian-4-yl, 1,3-oxathian-5-yl, 1,3-oxathian-6-yl,1,4-oxathian-2-yl, 1,4-oxathian-3-yl, 1,2-dithian-3-yl,1,2-dithian-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl,hexahydropyrimidin-5-yl, hexahydropyrazin-2-yl, hexahydropyridazin-3-yl,hexahydropyridazin-4-yl, tetrahydro-1,3-oxazin-2-yl,tetrahydro-1,3-oxazin-4-yl, tetrahydro-1,3-oxazin-5-yl,tetrahydro-1,3-oxazin-6-yl, tetrahydro-1,3-thiazin-2-yl,tetrahydro-1,3-thiazin-4-yl, tetrahydro-1,3-thiazin-5-yl,tetrahydro-1,3-thiazin-6-yl, tetrahydro-1,4-thiazin-2-yl,tetrahydro-1,4-thiazin-3-yl, tetrahydro-1,4-oxazin-2-yl,tetrahydro-1,4-oxazin-3-yl, tetrahydro-1,2-oxazin-3-yl,tetrahydro-1,2-oxazin-4-yl, tetrahydro-1,2-oxazin-5-yl,tetrahydro-1,2-oxazin-6-yl;N-bound, 5-membered, saturated rings, such astetrahydropyrrol-1-yl (pyrrolidin-1-yl), tetrahydropyrazol-1-yl,tetrahydroisoxazol-2-yl, tetrahydroisothiazol-2-yl,tetrahydroimidazol-1-yl, tetrahydrooxazol-3-yl, tetrahydrothiazol-3-yl;N-bound, 6-membered, saturated rings, such aspiperidin-1-yl, hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl(piperazin-1-yl), hexahydropyridazin-1-yl, tetrahydro-1,3-oxazin-3-yl,tetrahydro-1,3-thiazin-3-yl, tetrahydro-1,4-thiazin-4-yl,tetrahydro-1,4-oxazin-4-yl(morpholin-1-yl), tetrahydro-1,2-oxazin-2-yl;C-bound, 5-membered, partially unsaturated rings, such as2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,5-dihydrofuran-2-yl,2,5-di-hydrofuran-3-yl, 4,5-dihydrofuran-2-yl, 4,5-dihydrofuran-3-yl,2,3-dihydro-thien-2-yl, 2,3-dihydrothien-3-yl, 2,5-dihydrothien-2-yl,2,5-dihydrothien-3-yl, 4,5-dihydrothien-2-yl, 4,5-dihydrothien-3-yl,2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl,2,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-3-yl,4,5-dihydro-1H-pyrrol-2-yl, 4,5-dihydro-1H-pyrrol-3-yl,3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-3-yl,3,4-dihydro-5H-pyrrol-2-yl, 3,4-dihydro-5H-pyrrol-3-yl,4,5-dihydro-1H-pyrazol-3-yl, 4,5-dihydro-1H-pyrazol-4-yl,4,5-dihydro-1H-pyrazol-5-yl, 2,5-dihydro-1H-pyrazol-3-yl,2,5-dihydro-1H-pyrazol-4-yl, 2,5-dihydro-1H-pyrazol-5-yl,4,5-dihydroisoxazol-3-yl, 4,5-dihydroisoxazol-4-yl,4,5-dihydroisoxazol-5-yl, 2,5-dihydroisoxazol-3-yl,2,5-dihydroisoxazol-4-yl, 2,5-dihydroisoxazol-5-yl,2,3-dihydroisoxazol-3-yl, 2,3-dihydroisoxazol-4-yl,2,3-dihydroisoxazol-5-yl, 4,5-dihydroisothiazol-3-yl,4,5-dihydroisothiazol-4-yl, 4,5-dihydroisothiazol-5-yl,2,5-dihydroisothiazol-3-yl, 2,5-dihydroisothiazol-4-yl,2,5-dihydroisothiazol-5-yl, 2,3-dihydroisothiazol-3-yl,2,3-dihydroisothiazol-4-yl, 2,3-dihydroisothiazol-5-yl,4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-4-yl,4,5-dihydro-1H-imidazol-5-yl, 2,5-dihydro-1H-imidazol-2-yl,2,5-dihydro-1H-imidazol-4-yl, 2,5-dihydro-1H-imidazol-5-yl,2,3-dihydro-1H-imidazol-2-yl, 2,3-dihydro-1H-imidazol-4-yl,4,5-dihydro-oxazol-2-yl, 4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl,2,5-dihydrooxazol-2-yl, 2,5-dihydrooxazol-4-yl, 2,5-dihydrooxazol-5-yl,2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl,4,5-dihydrothiazol-2-yl, 4,5-dihydrothiazol-4-yl,4,5-dihydrothiazol-5-yl, 2,5-dihydrothiazol-2-yl,2,5-dihydrothiazol-4-yl, 2,5-dihydrothiazol-5-yl,2,3-dihydrothiazol-2-yl, 2,3-dihydrothiazol-4-yl,2,3-dihydrothiazol-5-yl, 1,3-dioxol-2-yl, 1,3-dioxol-4-yl,1,3-dithiol-2-yl, 1,3-dithiol-4-yl, 1,3-oxathiol-2-yl,1,3-oxathiol-4-yl, 1,3-oxathiol-5-yl;C-bound, 6-membered, partially unsaturated rings, such as2H-3,4-dihydropyran-6-yl, 2H-3,4-dihydropyran-5-yl,2H-3,4-dihydropyran-4-yl, 2H-3,4-dihydropyran-3-yl,2H-3,4-dihydropyran-2-yl, 2H-3,4-dihydrothiopyran-6-yl,2H-3,4-dihydrothiopyran-5-yl, 2H-3,4-dihydrothiopyran-4-yl,2H-3,4-dihydrothiopyran-3-yl, 2H-3,4-dihydrothiopyran-2-yl,1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,4-tetrahydropyridin-5-yl,1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetra-hydropyridin-3-yl,1,2,3,4-tetrahydropyridin-2-yl, 2H-5,6-dihydropyran-2-yl,2H-5,6-dihydropyran-3-yl, 2H-5,6-dihydropyran-4-yl,2H-5,6-dihydropyran-5-yl, 2H-5,6-dihydropyran-6-yl,2H-5,6-dihydrothiopyran-2-yl, 2H-5,6-dihydrothiopyran-3-yl,2H-5,6-dihydrothiopyran-4-yl, 2H-5,6-dihydrothiopyran-5-yl,2H-5,6-dihydrothiopyran-6-yl, 1,2,5,6-tetrahydropyridin-2-yl,1,2,5,6-tetrahydropyridin-3-yl, 1,2,5,6-tetrahydropyridin-4-yl,1,2,5,6-tetrahydropyridin-5-yl, 1,2,5,6-tetrahydropyridin-6-yl,2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl,2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl,2,3,4,5-tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl-,4H-pyran-4-yl, 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, 4H-thiopyran-4-yl,1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3-yl,1,4-dihydropyridin-4-yl, 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl,2H-pyran-5-yl, 2H-pyran-6-yl, 2H-thiopyran-2-yl, 2H-thiopyran-3-yl,2H-thiopyran-4-yl, 2H-thiopyran-5-yl, 2H-thiopyran-6-yl,1,2-dihydropyridin-2-yl, 1,2-dihydro-pyridin-3-yl,1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl,1,2-dihydro-pyridin-6-yl, 3,4-dihydropyridin-2-yl,3,4-dihydropyridin-3-yl, 3,4-dihydro-pyridin-4-yl,3,4-dihydropyridin-5-yl, 3,4-dihydropyridin-6-yl,2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl,2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl,2,5-dihydropyridin-6-yl, 2,3-dihydropyridin-2-yl,2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl,2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl,2H-5,6-dihydro-1,2-oxazin-3-yl, 2H-5,6-dihydro-1,2-oxazin-4-yl,2H-5,6-dihydro-1,2-oxazin-5-yl, 2H-5,6-dihydro-1,2-oxazin-6-yl,2H-5,6-dihydro-1,2-thiazin-3-yl, 2H-5,6-dihydro-1,2-thiazin-4-yl,2H-5,6-dihydro-1,2-thiazin-5-yl, 2H-5,6-dihydro-1,2-thiazin-6-yl,4H-5,6-dihydro-1,2-oxazin-3-yl, 4H-5,6-dihydro-1,2-oxazin-4-yl,4H-5,6-dihydro-1,2-oxazin-5-yl, 4H-5,6-dihydro-1,2-oxazin-6-yl,4H-5,6-dihydro-1,2-thiazin-3-yl, 4H-5,6-dihydro-1,2-thiazin-4-yl,4H-5,6-dihydro-1,2-thiazin-5-yl, 4H-5,6-dihydro-1,2-thiazin-6-yl,2H-3,6-dihydro-1,2-oxazin-3-yl, 2H-3,6-dihydro-1,2-oxazin-4-yl,2H-3,6-dihydro-1,2-oxazin-5-yl, 2H-3,6-dihydro-1,2-oxazin-6-yl,2H-3,6-dihydro-1,2-thiazin-3-yl, 2H-3,6-dihydro-1,2-thiazin-4-yl,2H-3,6-dihydro-1,2-thiazin-5-yl, 2H-3,6-dihydro-1,2-thiazin-6-yl,2H-3,4-dihydro-1,2-oxazin-3-yl, 2H-3,4-dihydro-1,2-oxazin-4-yl,2H-3,4-dihydro-1,2-oxazin-5-yl, 2H-3,4-dihydro-1,2-oxazin-6-yl,2H-3,4-dihydro-1,2-thiazin-3-yl, 2H-3,4-dihydro-1,2-thiazin-4-yl,2H-3,4-dihydro-1,2-thiazin-5-yl, 2H-3,4-dihydro-1,2-thiazin-6-yl,2,3,4,5-tetrahydropyridazin-3-yl, 2,3,4,5-tetrahydropyridazin-4-yl,2,3,4,5-tetrahydropyridazin-5-yl, 2,3,4,5-tetrahydropyridazin-6-yl,3,4,5,6-tetrahydropyridazin-3-yl, 3,4,5,6-tetrahydropyridazin-4-yl,1,2,5,6-tetrahydropyridazin-3-yl, 1,2,5,6-tetrahydropyridazin-4-yl,1,2,5,6-tetra-hydropyridazin-5-yl, 1,2,5,6-tetrahydropyridazin-6-yl,1,2,3,6-tetrahydro-pyridazin-3-yl, 1,2,3,6-tetrahydropyridazin-4-yl,4H-5,6-dihydro-1,3-oxazin-2-yl, 4H-5,6-dihydro-1,3-oxazin-4-yl,4H-5,6-dihydro-1,3-oxazin-5-yl, 4H-5,6-dihydro-1,3-oxazin-6-yl,4H-5,6-dihydro-1,3-thiazin-2-yl, 4H-5,6-dihydro-1,3-thiazin-4-yl,4H-5,6-dihydro-1,3-thiazin-5-yl, 4H-5,6-dihydro-1,3-thiazin-6-yl,3,4,5-6-tetrahydropyrimidin-2-yl, 3,4,5,6-tetrahydropyrimidin-4-yl,3,4,5,6-tetrahydropyrimidin-5-yl, 3,4,5,6-tetrahydropyrimidin-6-yl,1,2,3,4-tetrahydropyrazin-2-yl, 1,2,3,4-tetrahydropyrazin-5-yl,1,2,3,4-tetrahydro-pyrimidin-2-yl, 1,2,3,4-tetrahydropyrimidin-4-yl,1,2,3,4-tetrahydropyrimidin-5-yl, 1,2,3,4-tetrahydropyrimidin-6-yl,2,3-dihydro-1,4-thiazin-2-yl, 2,3-dihydro-1,4-thiazin-3-yl,2,3-dihydro-1,4-thiazin-5-yl, 2,3-dihydro-1,4-thiazin-6-yl,2H-1,3-oxazin-2-yl, 2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl,2H-1,3-oxazin-6-yl, 2H-1,3-thiazin-2-yl, 2H-1,3-thiazin-4-yl,2H-1,3-thiazin-5-yl, 2H-1,3-thiazin-6-yl, 4H-1,3-oxazin-2-yl,4H-1,3-oxazin-4-yl, 4H-1,3-oxazin-5-yl, 4H-1,3-oxazin-6-yl,4H-1,3-thiazin-2-yl, 4H-1,3-thiazin-4-yl, 4H-1,3-thiazin-5-yl,4H-1,3-thiazin-6-yl, 6H-1,3-oxazin-2-yl, 6H-1,3-oxazin-4-yl,6H-1,3-oxazin-5-yl, 6H-1,3-oxazin-6-yl, 6H-1,3-thiazin-2-yl,6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl, 6H-1,3-thiazin-6-yl,2H-1,4-oxazin-2-yl, 2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl,2H-1,4-oxazin-6-yl, 2H-1,4-thiazin-2-yl, 2H-1,4-thiazin-3-yl,2H-1,4-thiazin-5-yl, 2H-1,4-thiazin-6-yl, 4H-1,4-oxazin-2-yl,4H-1,4-oxazin-3-yl, 4H-1,4-thiazin-2-yl, 4H-1,4-thiazin-3-yl,1,4-dihydropyridazin-3-yl, 1,4-dihydropyridazin-4-yl,1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-6-yl,1,4-dihydropyrazin-2-yl, 1,2-dihydropyrazin-2-yl,1,2-dihydropyrazin-3-yl, 1,2-dihydropyrazin-5-yl,1,2-dihydropyrazin-6-yl, 1,4-dihydropyrimidin-2-yl,1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin-5-yl,1,4-dihydropyrimidin-6-yl, 3,4-dihydropyrimidin-2-yl,3,4-dihydropyrimidin-4-yl, 3,4-dihydropyrimidin-5-yl or3,4-dihydropyrimidin-6-yl;N-bound, 5-membered, partially unsaturated rings, such as2,3-dihydro-1H-pyrrol-1-yl, 2,5-dihydro-1H-pyrrol-1-yl,4,5-dihydro-1H-pyrazol-1-yl, 2,5-dihydro-1H-pyrazol-1-yl,2,3-dihydro-1H-pyrazol-1-yl, 2,5-dihydroisoxazol-2-yl,2,3-dihydroisoxazol-2-yl, 2,5-dihydroisothiazol-2-yl,2,3-dihydroisoxazol-2-yl, 4,5-dihydro-1H-imidazol-1-yl,2,5-dihydro-1H-imidazol-1-yl, 2,3-dihydro-1H-imidazol-1-yl,2,3-dihydrooxazol-3-yl, 2,3-dihydrothiazol-3-yl;N-bound, 6-membered, partially unsaturated rings, such as1,2,3,4-tetrahydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl,1,4-dihydro-pyridin-1-yl, 1,2-dihydropyridin-1-yl,2H-5,6-dihydro-1,2-oxazin-2-yl, 2H-5,6-dihydro-1,2-thiazin-2-yl,2H-3,6-dihydro-1,2-oxazin-2-yl, 2H-3,6-dihydro-1,2-thiazin-2-yl,2H-3,4-dihydro-1,2-oxazin-2-yl, 2H-3,4-dihydro-1,2-thiazin-2-yl,2,3,4,5-tetrahydropyridazin-2-yl, 1,2,5,6-tetrahydropyridazin-1-yl,1,2,5,6-tetrahydropyridazin-2-yl, 1,2,3,6-tetrahydropyridazin-1-yl,3,4,5,6-tetrahydropyrimidin-3-yl, 1,2,3,4-tetrahydropyrazin-1-yl,1,2,3,4-tetrahydropyrimidin-1-yl, 1,2,3,4-tetrahydropyrimidin-3-yl,2,3-dihydro-1,4-thiazin-4-yl, 2H-1,2-oxazin-2-yl, 2H-1,2-thiazin-2-yl,4H-1,4-oxazin-4-yl, 4H-1,4-thiazin-4-yl, 1,4-dihydropyridazin-1-yl,1,4-dihydropyrazin-1-yl, 1,2-dihydropyrazin-1-yl,1,4-dihydropyrimidin-1-yl or 3,4-dihydropyrimidin-3-yl;C-bound, 5-membered, heteroaromatic rings, such as2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrrol-2-yl, pyrrol-3-yl,pyrazol-3-yl, pyrazol-4-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl,isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl,imidazol-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,1,2,4-oxadiazol-3-yl, 1,2,4,-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazolyl-2-yl, 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl, tetrazol-5-yl;C-bound, 6-membered, heteroaromatic rings, such aspyridin-2-yl, pyridin-3-yl, pyridin-4-yl (4-pyridyl), pyridazin-3-yl,pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,pyrazin-2-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,4,5-tetrazin-3-yl;N-bound, 5-membered, heteroaromatic rings, such aspyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl,1,2,4-triazol-1-yl, tetrazol-1-yl.

Heterocyclyl also includes bicyclic heterocycles, which comprise one ofthe described 5- or 6-membered heterocyclic rings and a furtheranellated, saturated or unsaturated or aromatic carbocycle, such as abenzene, cyclohexane, cyclohexene or cyclohexadiene ring, or a furtheranellated 5- or 6-membered heterocyclic ring, this heterocyclic ringbeing saturated or unsaturated or aromatic. These include quinolinyl,isoquinolinyl, indolyl, indolizinyl, isoindolyl, indazolyl, benzofuryl,benzothienyl, benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl andbenzimidazolyl. Examples of 5- or 6-membered heteroaromatic compoundscomprising an anellated cycloalkenyl ring include dihydroindolyl,dihydroindolizinyl, dihydroisoindolyl, dihydrochinolinyl,dihydroisoquinolinyl, chromenyl and chromanyl.

C₃-C₁₂-Heteroarylene is a heteroaryl diradical. Examples includepyrid-2,5-ylene and pyrid-2,4-ylene.

With respect to the compounds' capability of inhibiting glycinetransporter 1, the variables A, R, R¹, W, A¹, Q, Y, A², X¹, R², R³, R⁴,X², X³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, n preferablyhave the following meanings which, when taken alone or in combination,represent particular embodiments of the heterocyclic compounds of theformula (I) or any other formula disclosed herein.

In said formula (I), there may be one or more than one substituent R, R²and/or R³. More particularly, there may be up to 3 substituents R², andup to 5 substituents R³. Preferably there is one substituent R and 1, 2or 3 substituents R². Formula (I) may thus be depicted as follows:

wherein a is 1, 2 or 3, b is 1, 2, 3, 4 or 5 and c is 1. If there ismore than one radical R², these may be the same or different radicals.If there is more than one radical R³, these may be the same or differentradicals.

A is a 5- or 6-membered heterocyclic ring which includes two carbonatoms from the cyclic moiety to which A is fused. The ring may besaturated, unsaturated non-aromatic or aromatic. As a heterocyclic ring,A may include 1, 2 or 3 heteroatoms as ring member atoms, which areselected, independently of each other from N, S and O. Preferredheterocyclic rings comprise 1 nitrogen atom as ring member atom andoptionally 1 or 2 further heteroatoms as ring members, which areselected, independently of each other from O, S and N. Likewisepreferred heterocyclic radicals comprise 1 heteroatom as ring memberatom, which is selected from O, S and N, and optionally 1 or 2 furthernitrogen atoms as ring member atoms. According to a particularembodiment, A is a heterocyclic ring selected from the group consistingof the following 5- or 6-membered heterocyclic rings:

In said formulae, hydrogen atoms are not depicted. This is meant toillustrate that the free valency of a carbon or nitrogen atom may beeither bound to a hydrogen atom, to R or to R². Accordingly, R and R²may be C- or N-bound at any position of ring A.

The skilled person will appreciate that some of the rings depicted abovemay be represented with a different structure, e.g. with hydrogen atomshaving other positions than those shown above, for instance as given inthe following structures:

Preferably, A is a heterocyclic ring selected from the group consistingof the following 5- or 6-membered heterocyclic rings:

According to a further particular embodiment, A is a heterocyclic ringselected from the group consisting of the following 5- or 6-memberedheterocyclic rings:

According to a preferred embodiment, A is a heterocyclic ring selectedfrom the group consisting of the following 5- or 6-membered heterocyclicrings:

If ring A is a 5-membered heterocyclic ring it is preferred that R isbound to G¹ or G², in particular G²:

In said formula, G¹, G² and G³ independently are —CH═, —CH₂—, —N═, —NH—,S or O, the dotted line represents a single or a double bond and R³, R⁴,X², X³, R⁵ are as defined herein.

If ring A is 6-membered heterocyclic ring it is preferred that R isbound to G¹ or G², in particular G²:

In said formula, G¹, G², G³ and G⁴ independently are —CH═, —CH₂—, —N═,—NH—, S or O, the dotted line represents a single or a double bond andR³, R⁴, X², X³, R⁵ are as defined herein.

Heterocyclic compounds having the following partial structures arepreferred:

Heterocyclic compounds having the following partial structures areparticularly preferred:

In said formulae, R and R² are as defined herein. If there is more thanone radical R², these may be the same or different radicals.

According to a particular embodiment, the partial structures depictedabove are fused with a tetrahydropyridine moiety (i.e., n is 1). Thesame applies to the preferred and particular embodiments disclosed forring A.

According to one embodiment, R is NC-A¹-X¹—, in particular cyano (i.e.A¹ and X¹ are both a bond).

Preferably, R is R¹—W-A¹-Q-Y-A²-X¹—, and A, R¹, W, A¹, Q, Y, A², X¹, R²,R³, R⁴, X², X³, R⁵ are as defined herein.

R¹ is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl or n-butyl, afurther example being isopropyl or sec-butyl),C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl), halogenatedC₁-C₆-alkyl (e.g. 3-fluoroprop-1-yl), hydroxy-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₁-C₆-alkylcarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkyl, (optionally substitutedC₆-C₁₂-aryl-C₁-C₆-alkyl)amino-C₁-C₄-alkyl, optionally substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl, optionally substitutedC₃-C₁₂-heterocyclyl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl (e.g. cyclobutyl),C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, halogenatedC₁-C₆-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl, aminocarbonyl,C₁-C₆-alkylaminocarbonyl, (halogenated C₁-C₄-alkyl)aminocarbonyl,C₆-C₁₂-arylaminocarbonyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionallysubstituted C₆-C₁₂-aryl (e.g. phenyl), hydroxy, C₁-C₆-alkoxy,halogenated C₁-C₆-alkoxy, C₁-C₆-hydroxyalkoxy,C₁-C₆-alkoxy-C₁-C₄-alkoxy, amino-C₁-C₄-alkoxy,C₁-C₆-alkylamino-C₁-C₄-alkoxy, di-C₁-C₆-alkylamino-C₁-C₄-alkoxy,C₁-C₆-alkylcarbonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylcarbonylamino-C₁-C₄-alkoxy,C₁-C₆-alkoxycarbonylamino-C₁-C₄-alkoxy, C₆-C₁₂-aryl-C₁-C₄-alkoxy,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkoxy, (halogenatedC₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylsulfonylamino-C₁-C₄-alkoxy,(C₆-C₁₂-aryl-C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclylsulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclyl-C₁-C₄-alkoxy, C₆-C₁₂-aryloxy,C₃-C₁₂-heterocyclyloxy, C₁-C₆-alkylthio, halogenated C₁-C₆-alkylthio,C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino, di-C₁-C₆-alkylamino,di-(halogenated C₁-C₆-alkyl)amino, C₁-C₆-alkylcarbonylamino,(halogenated C₁-C₆-alkyl)carbonylamino, C₆-C₁₂-arylcarbonylamino,C₁-C₆-alkylsulfonylamino, (halogenated C₁-C₆-alkyl)sulfonylamino,C₆-C₁₂-arylsulfonylamino or optionally substituted C₃-C₁₂-heterocyclyl(e.g. 3-pyridyl, 1-methyl-1,2-diazol-4-yl or 1-methyl-1,3-diazol-4-yl, afurther example being 2-pyridyl or 4-pyridyl).

Preferably, R¹ is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl orn-butyl, a further example being isopropyl or sec-butyl),C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl), halogenatedC₁-C₆-alkyl (e.g. 3-fluoroprop-1-yl), C₁-C₆-alkoxy-C₁-C₄-alkyl,amino-C₁-C₄-alkyl, C₁-C₆-alkylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl, C₆-C₁₂-aryl-C₁-C₄-alkyl,C₃-C₁₂-cycloalkyl (e.g. cyclobutyl), C₂-C₆-alkenyl, optionallysubstituted C₆-C₁₂-aryl (e.g. phenyl), hydroxy, C₁-C₆-alkylamino,(halogenated C₁-C₆-alkyl)amino, di-C₁-C₆-alkylamino or optionallysubstituted C₃-C₁₂-heterocyclyl (e.g. 3-pyridyl,1-methyl-1,2-diazol-4-yl or 1-methyl-1,3-diazol-4-yl, a further examplebeing 2-pyridyl or 4-pyridyl).

In particular, R¹ is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl, n-propylor n-butyl, a further example being isopropyl or sec-butyl),C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl), halogenatedC₁-C₆-alkyl (e.g. 3-fluoroprop-1-yl), C₃-C₁₂-cycloalkyl (e.g.cyclobutyl), optionally substituted C₆-C₁₂-aryl (e.g. phenyl) oroptionally substituted C₃-C₁₂-heterocyclyl (e.g. 3-pyridyl,1-methyl-1,2-diazol-4-yl or 1-methyl-1,3-diazol-4-yl, a further examplebeing 2-pyridyl or 4-pyridyl).

In connection with R¹, substituted C₆-C₁₂-aryl in particular includesC₆-C₁₂-aryl, such as phenyl or naphthyl, substituted with 1, 2 or 3substituents selected from the group consisting of halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, amino,C₁-C₄-alkylamino, C₁-C₄-dialkylamino, morpholino and piperidinyl. Thesame applies to substituted C₆-C₁₂-aryl in substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl.

In connection with R¹, substituted C₃-C₁₂-heterocyclyl in particularincludes C₃-C₁₂-heterocyclyl, such as pyridyl, thienyl, diazolyl,quinolinyl, piperidinyl, piperazinyl or morpholinyl, substituted with 1,2 or 3 substituents selected from the group consisting of halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxycarbonyl, cyano, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, C₁-C₄-alkylsulfonyl, amino, C₁-C₄-alkylamino,C₁-C₄-dialkylamino, C₆-C₁₂-arylamino and C₃-C₁₂-heterocyclyl (e.g.,morpholino or piperidinyl). The same applies to substitutedC₃-C₁₂-heteroaryl in substituted C₃-C₁₂-heteroaryl-C₁-C₄-alkyl.

According to one embodiment, W is —NR⁸— and Y is a bond. According to analternative embodiment, W is a bond and Y is —NR⁹—. According to afurther alternative embodiment, W is a bond and Y is a bond, especiallyif R¹ is a nitrogen-bound radical, e.g. nitrogen-bound heterocyclyl suchas piperazinyl or morpholinyl.

According to one embodiment, Q is —S(O)₂—. According to an alternativeembodiment, Q is —C(O)—. If Q is a bond, at least one of W and Y is nota bond, e.g., W is a bond and Y is —NR⁹—.

According to a particular embodiment, —W-A¹-Q-Y— is —W-A¹-S(O)₂—NR⁹—,—NR⁸—S(O)₂—, -A¹-S(O)₂— or —S(O)₂—. According to a further particularembodiment, —W-A¹-Q-Y— is —W-A¹-CO—NR⁹— or —NR⁸—CO—.

A¹ is optionally substituted C₁-C₄-alkylene or a bond. In connectionwith A¹, substituted C₁-C₄-alkylene in particular includesC₁-C₄-alkylene substituted with 1, 2 or 3 substituents selected from thegroup consisting of halogen, C₁-C₄-alkyl and cyano. Preferably, A¹ is abond. If A¹ is C₁-C₄-alkylene, W is preferably —NR⁸—.

A² is optionally substituted C₁-C₄-alkylene (e.g. methylene or1,2-ethylene, a further example being 1,3-propylene),C₁-C₄-alkylene-CO—, —CO—C₁-C₄-alkylene, C₁-C₄-alkylene-O—C₁-C₄-alkylene,C₁-C₄-alkylene-NR¹⁰—C₁-C₄-alkylene, optionally substitutedC₆-C₁₂-arylene, optionally substituted C₆-C₁₂-heteroarylene or a bond.Additionally, A² may be optionally substituted C₂-C₄-alkenylen oroptionally substituted C₂-C₄-alkynylene. Preferably, A² is optionallysubstituted C₁-C₄-alkylene (e.g. methylene or 1,2-ethylene, a furtherexample being 1,3-propylene). More preferably, A² is C₁-C₄-alkylene(e.g. methylene or 1,2-ethylene, a further example being 1,3-propylene).Alternatively, it is preferred that A² is optionally substitutedC₆-C₁₂-arylene, in particular C₆-C₁₂-arylene selected from the groupconsisting of phen-1,4-ylene and phen-1,3-ylene, or optionallysubstituted C₆-C₁₂-heteroarylene, in particular C₆-C₁₂-heteroaryleneselected from the group consisting of pyrid-2,5-ylene andpyrid-2,4-ylene. If A² is a bond, X¹ is preferably optionallysubstituted C₁-C₄-alkylene. Alternatively, if A² is a bond, X¹ is inparticular optionally substituted C₂-C₄-alkenylene or optionallysubstituted C₂-C₄-alkynylene.

In connection with A², substituted C₁-C₄-alkylene in particular includesC₁-C₄-alkylene substituted with 1, 2 or 3 substituents selected from thegroup consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyano.

In connection with A², substituted C₂-C₄-alkenylene or substitutedC₂-C₄-alkynylene in particular includes C₂-C₄-alkenylene orC₂-C₄-alkynylene substituted with 1, 2 or 3 substituents selected fromthe group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyano.

In connection with A², substituted C₆-C₁₂-arylene in particular includesC₆-C₁₂-arylene substituted with 1, 2 or 3 substituents selected from thegroup consisting of C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxycarbonyl,cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylsulfonyl, amino,C₁-C₄-alkylamino, C₁-C₄-dialkylamino, C₆-C₁₂-arylamino andC₃-C₁₂-heterocyclyl (e.g., morpholino or piperidinyl).

In connection with A², substituted C₆-C₁₂-heteroarylene in particularincludes C₆-C₁₂-heteroarylene substituted with 1, 2 or 3 substituentsselected from the group consisting of C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxycarbonyl, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylsulfonyl, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino,C₆-C₁₂-arylamino and C₃-C₁₂-heterocyclyl (e.g., morpholino orpiperidinyl).

X¹ is —O—, —NR¹¹—, —S— optionally substituted C₁-C₄-alkylene (e.g.—CH₂—) or a bond. In connection with X¹, substituted C₁-C₄-alkylene inparticular includes C₁-C₄-alkylene substituted with 1, 2 or 3substituents selected from the group consisting of halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl and cyano. Additionally, X¹ may be optionallysubstituted C₂-C₄-alkenylen or optionally substituted C₂-C₄-alkynylene(e.g. propynylene). In connection with X¹, substituted C₂-C₄-alkenyleneor substituted C₂-C₄-alkynylene in particular includes C₂-C₄-alkenyleneor C₂-C₄-alkynylene substituted with 1, 2 or 3 substituents selectedfrom the group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl andcyano. According to one embodiment, X¹ is —O—, —NR¹¹ or —S—, inparticular —O—. According to another embodiment, X¹ is a bond.Alternatively, it is preferred if X¹ is optionally substitutedC₁-C₄-alkylene (e.g. —CH₂—, 1,2-ethylene and 1,3-propylene).

According to a particular embodiment, A² is a bond and X¹ is optionallysubstituted C₁-C₄-alkylene, optionally substituted C₂-C₄-alkenylene oroptionally substituted C₂-C₄-alkynylene.

According to a particular embodiment, the structural element —Y-A²-X¹—comprises at least 2, 3 or 4 atoms in the main chain. According tofurther particular embodiments the structural element —Y-A²-X¹— has upto 4, 5 or 6 atoms in the main chain, such as 2 to 6, 2 to 5 or 2 to 4atoms in the main chain, especially 2, 3 or 4 atoms in the main chain.

According to a particular embodiment, R¹—W-A¹-Q-Y-A²-X¹— isR¹—S(O)₂—NH-A²-X¹—, R¹—NH—S(O)₂-A²-X¹—, R¹—C(O)—NH-A²-X¹—,R¹—NH—C(O)-A²-X¹— or R¹—NH-A²-X¹—.

According to a further particular embodiment, —Y-A²-X¹— is—C₁-C₄-alkylene-O— or —NR⁹—C₁-C₄-alkylene-O—, with —Y-A²-X¹— preferablyhaving 2 to 6, 3 to 5 and especially 4 atoms in the main chain.Particular examples of —Y-A²-X¹— include —(CH₂)₃—O— and —NR⁹—(CH₂)₂—O—.In this particular embodiment, R⁹ is as defined herein and preferably R⁹is hydrogen, C₁-C₆-alkyl (e.g. methyl or ethyl) or C₃-C₁₂-cycloalkyl(e.g. cyclopropyl), or R⁹ is C₁-C₄-alkylene that is bound to a carbonatom in A² which is C₁-C₄-alkylene.

According to a further particular embodiment, —Y-A²-X¹— is—NR⁹—C₁-C₄-alkylene- (e.g. —NH—CH₂—, a further example being —NH—(CH₂)₂—or —NH—(CH₂)₃—), with —Y-A²-X¹— preferably having 2 to 6, 3 to 5 andespecially 2, 3 or 4 atoms in the main chain. In this particularembodiment, R⁹ is as defined herein and preferably R⁹ is hydrogen,C₁-C₆-alkyl (e.g. methyl) or C₃-C₁₂-heterocyclyl (e.g. 3-azetidinyl); orR⁹ is C₁-C₄-alkylene that is bound to a carbon atom in A² which isC₁-C₄-alkylene.

According to a further particular embodiment, —Y-A²-X¹— is—NR⁹—C₂-C₄-alkenylene- or —NR⁹—C₂-C₄-alkynylene- (e.g. —NH—CH₂—C≡C—),with —Y-A²-X¹— preferably having 2 to 6, 3 to 5 and especially 4 atomsin the main chain. In this particular embodiment, R⁹ is as definedherein and preferably is R⁹ is hydrogen, C₁-C₆-alkyl (e.g. methyl orethyl) or C₃-C₁₂-cycloalkyl (e.g. cyclopropyl or cyclobutyl).

According to a further particular embodiment, —Y-A²-X¹— is—C₁-C₄-alkylene- (e.g. —(CH₂)₂—), with —Y-A²-X¹— preferably having 2 to6, 2 to 5, 2 to 4 and especially 2 atoms in the main chain. If A is aheterocyclic ring, this embodiment of —Y-A²-X¹— is particularlysuitable.

According to a further particular embodiment, the structural motif—Y-A²-X¹ as disclosed herein is bound to Q being —S(O)₂— or —C(O)—.Particular examples for this embodiment include heterocyclic compoundsof the invention wherein R is R¹—S(O)₂—Y-A²-X¹ or R¹—C(O)—Y-A²-X¹.

The radical R and in particular the radical R¹—W-A¹-Q-Y-A²-X¹— may, inprinciple, be bound to any position of the heterocyclic ring A.Particular examples include:

Further particular examples include:

In said formulae, R¹, W, A¹, Q, Y, A², X¹, R², R³, R⁴, X², X³, R⁵, n areas defined herein.

Further particular examples include heterocyclic compounds of the aboveformulae wherein the radical R¹—W-A¹-Q-Y-A²-X¹— is replaced by theradical —CN.

In addition to the radical R¹—W-A¹-Q-Y-A²-X—, the heterocyclic compoundsof the invention may have one or more than one further substituent boundto the heterocyclic ring A. In these positions, the skeleton of theheterocyclic compounds may thus be substituted with one or more than oneradical R². If there is more than one radical R², these may be the sameor different radicals.

R² is hydrogen, halogen, C₁-C₆-alkyl, halogenated C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, —CN, C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionallysubstituted C₆-C₁₂-aryl, hydroxy, C₁-C₆-alkoxy, halogenatedC₁-C₆-alkoxy, C₁-C₆-alkoxycarbonyl, C₂-C₆-alkenyloxy,C₆-C₁₂-aryl-C₁-C₄-alkoxy, C₁-C₆-alkylcarbonyloxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, aminosulfonyl, amino,C₁-C₆-alkylamino, C₂-C₆-alkenylamino, nitro or optionally substitutedC₃-C₁₂-heterocyclyl, or two radicals R² together with the ring atoms ofA to which they are bound form an optionally substituted 5- or6-membered ring.

In connection with R², substituted C₆-C₁₂-aryl in particular includesC₆-C₁₂-aryl, such as phenyl, substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen and C₁-C₄-alkyl,C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

In connection with R², substituted C₃-C₁₂-heterocyclyl in particularincludes C₃-C₁₂-heterocyclyl, such as morpholinyl, pyrrolidinyl andpiperidinyl, substituted with 1, 2 or 3 substituents selected from thegroup consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, cyano,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

An optionally substituted 5- or 6-membered ring that is formed by tworadicals R² together with the ring atoms of A to which they are boundis, for instance, a benzene ring.

Preferably, R² is hydrogen, halogen, or C₁-C₆-alkoxy. In particular, R²is hydrogen.

In 1-, 3-, 4- and/or 5-(if n is 2) position, the heterocyclic compoundsof the invention may be substituted with one or more than one radicalR³. If there is more than one radical R³, these may be the same ordifferent radicals. The heterocyclic compounds of the invention maytherefore be represented by the following formula.

wherein R^(3a), R^(3b), R^(3c), R^(3d), R^(3e) independently have one ofthe meanings given for R³, and A, R, R², R³, R⁴, X², X³, R⁵, n are asdefined herein.

According to a particular embodiment, the heterocyclic compounds of theinvention have one of the following formulae:

wherein R^(3a), R^(3b), R^(3e) independently have the meaning of R³ andA, R, R², R³, R⁴, X², X³, R⁵, n are as defined herein.

R³ is hydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, or two radicals R³together with the carbon atom to which they are attached form a carbonylgroup.

Preferably, R³ is hydrogen or C₁-C₆-alkyl. In particular, R³ ishydrogen.

R⁴ is hydrogen, C₁-C₆-alkyl, halogenated C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl, CH₂CN,—CHO, C₁-C₄-alkylcarbonyl, (halogenated C₁-C₄-alkyl)carbonyl,C₁-C₄-alkoxycarbonyl (e.g. t-butyloxycarbonyl), C₆-C₁₂-arylcarbonyl,C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl, —C(═NH)NH₂, —C(═NH)NHCN,C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, amino or C₃-C₁₂-heterocyclyl.

Preferably, R⁴ is hydrogen, C₁-C₆-alkyl, halogenated C₁-C₄-alkyl,amino-C₁-C₄-alkyl, CH₂CN, C₁-C₄-alkylcarbonyl, (halogenatedC₁-C₄-alkyl)carbonyl, C₁-C₄-alkoxycarbonyl (e.g. t-butyloxycarbonyl),—C(═NH)NH₂, —C(═NH)NHCN, C₁-C₆-alkylsulfonyl, amino orC₃-C₁₂-heterocyclyl.

X² is —O—, —NR⁶—, —S—, >CR^(12a)CR^(12b) or a bond. Preferably, X² is>CR^(12a)R^(12b).

X³ is —O—, —S—, >CR^(13a)R^(13b) or a bond. Preferably, X³ is a bond.

Thus, it is preferred if X² is >CR^(12a)R^(12b) and X³ is a bond.

R^(12a) is hydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy. In particular, R^(12a) is hydrogen or C₁-C₆-alkyl.

R^(13a) is hydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy. In particular, R^(13a) is hydrogen or C₁-C₆-alkyl.

In connection with R^(12a) and R^(13a), substituted C₁-C₆-alkyl inparticular includes C₁-C₆-alkyl substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen, hydroxy, C₁-C₄-alkoxy andamino.

In connection with R^(12a) and R^(13a), substituted C₆-C₁₂-aryl inparticular includes C₆-C₁₂-aryl, such as phenyl, substituted with 1, 2or 3 substituents selected from the group consisting of C₁-C₄-alkyl,C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

R^(12b) is hydrogen or C₁-C₆-alkyl. According to a particularembodiment, R^(12b) is hydrogen.

R^(13b) is hydrogen or C₁-C₆-alkyl. According to a particularembodiment, R^(13b) is hydrogen.

Alternatively, R^(12a) and R^(12b), or R^(13a) and R^(13b), together aretogether are carbonyl or, preferably, optionally substitutedC₁-C₄-alkylene (e.g. 1,3-propylene), wherein one —CH₂— of C₁-C₄-alkylenemay be replaced by an oxygen atom or —NR¹⁴—.

In connection with R^(12a) and R^(12b), or R^(13a) and R^(13b),substituted C₁-C₄-alkylene in particular includes C₁-C₄-alkylenesubstituted with 1, 2 or 3 substituents selected from the groupconsisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxyand C₁-C₄-haloalkoxy.

According to a particular embodiment, R^(12a) is C₁-C₆-alkyl and R^(12b)is hydrogen or C₁-C₆-alkyl, or R^(13a) is C₁-C₆-alkyl and R^(13b) ishydrogen or C₁-C₆-alkyl.

According to a further particular embodiment, R^(12a) is hydrogen andR^(12b) is hydrogen, or R^(13a) is hydrogen and R^(13b) is hydrogen.

According to a further particular embodiment, R^(12a) and R^(12b)together are optionally substituted 1,3-propylene, or R^(13a) andR^(13b) together are optionally substituted 1,3-propylene.

R⁵ is optionally substituted C₆-C₁₂-aryl (e.g. 4-chlorophenyl, a furtherexample being phenyl), optionally substituted C₃-C₁₂-cycloalkyl oroptionally substituted C₃-C₁₂-heterocyclyl.

In connection with R⁵, substituted C₃-C₁₂-cycloalkyl in particularincludes C₃-C₁₂-cycloalkyl, such as cyclopropyl or cyclohexyl,substituted with 1, 2 or 3 substituents selected from the groupconsisting of halogen, optionally substituted C₁-C₆-alkyl, halogenatedC₁-C₆-alkyl, CN, hydroxy, C₁-C₆-alkoxy, halogenated C₁-C₆-alkoxy, amino,C₁-C₆-alkylamino, di-C₁-C₆-alkylamino and C₃-C₁₂-heterocyclyl.

In connection with R⁵, substituted C₆-C₁₂-aryl in particular includesC₆-C₁₂-aryl, such as phenyl, substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen (e.g. F, Cl, Br),optionally substituted C₁-C₆-alkyl (e.g. methyl), halogenatedC₁-C₆-alkyl (e.g. trifluormethyl), CN, hydroxy, C₁-C₆-alkoxy (e.g.methoxy), halogenated C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino and C₃-C₁₂-heterocyclyl.

In connection with R⁵, substituted C₃-C₁₂-heterocyclyl in particularincludes C₃-C₁₂-heterocyclyl substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen, optionally substitutedC₁-C₆-alkyl, halogenated C₁-C₆-alkyl, CN, hydroxy, C₁-C₆-alkoxy,halogenated C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylaminoand C₃-C₁₂-heterocyclyl.

In connection with R⁵, C₃-C₁₂-heterocyclyl in particular isC₃-C₁₂-heteroaryl.

Preferably, R⁵ is optionally substituted C₆-C₁₂-aryl, in particular asin heterocyclic compounds of the formula:

wherein A, R, R², R³, R⁴, X², X³, n are as defined herein; and

R^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f)

independently are hydrogen, halogen (e.g. chloro), optionallysubstituted C₁-C₆-alkyl, halogenated C₁-C₆-alkyl, CN, hydroxy,C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylamino orC₃-C₁₂-heterocyclyl.

According to a particular embodiment, the invention relates toheterocyclic compounds of the formula:

wherein A, R, R², R³, R⁴, R⁵, n are as defined herein, R⁵ preferablybeing optionally substituted aryl and in particular optionallysubstituted phenyl as disclosed herein.

In connection with R⁵ or R^(15a), R^(15b), R^(15c), R^(15d), R^(15e),substituted C₁-C₆-alkyl in particular includes C₁-C₆-alkyl, especiallyC₁-C₄-alkyl, substituted with 1, 2 or 3 substituents selected from thegroup consisting of hydroxy, C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino and C₃-C₁₂-heterocyclyl (e.g. morpholinyl orpiperidinyl).

According to a particular embodiment, R^(15a), R^(15b), R^(15d), R^(15e)are hydrogen and R^(15c) is different from hydrogen(para-mono-substitution).

According to a further particular embodiment, R^(15a), R^(15c), R^(15d),R^(15e) are hydrogen and R^(15b) is different from hydrogen(meta-mono-substitution).

In connection with R^(15a), R^(15b), R^(15c), R^(15d), R^(15e),C₃-C₁₂-heterocyclyl in particular includes morpholinyl, imidazolyl andpyrazolyl.

The index n is 0, 1 or 2. According to a particular embodiment, n is 1.

R⁶ is hydrogen or C₁-C₆-alkyl. Preferably, R⁶ is hydrogen.

R⁷ is hydrogen or C₁-C₆-alkyl. Preferably, R⁷ is hydrogen.

R⁹ is hydrogen or C₁-C₆-alkyl. Preferably, R⁹ is hydrogen.

R⁹ is hydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl, amino-C₁-C₆-alkyl,optionally substituted C₆-C₁₂-aryl-C₁-C₄-alkyl or C₃-C₁₂-heterocyclyl(e.g. 3-azetidinyl). Preferably, R⁹ is hydrogen or C₁-C₆-alkyl.

According to a particular embodiment, R⁹ and R¹ together areC₁-C₄-alkylene (e.g. 1,3-propylene) so as that R⁹ and R¹ together withthe atom in Q to which R¹ is bound and the nitrogen atom to which R⁹ isbound form an heterocyclic ring having, in particular, 4, 5 or 6 ringmember atoms (including the nitrogen atom and Q). With W and A¹ bothbeing a bond, such a ring may be represented by the following partialstructure:

wherein Q is as defined herein (e.g. S(O)₂) and n is 0, 1, 2, 3 or 4

According to a further particular embodiment, R⁹ is C₁-C₄-alkylene (e.g.methylene or 1,3-propylene) that is bound to a carbon atom in A² and A²is C₁-C₄-alkylene so that R⁹ and at least part of A² together with thenitrogen atom to which R⁹ is bound form an N-containing heterocyclicring having, in particular, 4, 5, 6 or 7 ring member atoms (includingthe nitrogen atom). Such a ring may be represented by the followingpartial structure:

wherein R¹, W, A¹, Q and X¹ are as defined herein, p is 1 or 2, r is 0,1 or 2 and q is 0, 1 or 2. In this particular embodiment, X¹ preferablyis —O—. Particular combinations of p, r and q include p=1, r=0, q=1; andp=1, r=0, q=0. Alternatively, p is 0, r is 3 and q is 1, with X¹preferably being —O—.

According to a further particular embodiment, R⁹ is C₁-C₄-alkylene (e.g.methylene or 1,3-propylene) that is bound to a carbon atom in X¹ and X¹is C₁-C₄-alkylene so that R⁹ and at least part of X¹ together with thenitrogen atom to which R⁹ is bound form an N-containing heterocyclicring having, in particular, 4, 5, 6 or 7 ring member atoms (includingthe nitrogen atom). With A² being a bond, such a ring may be representedby the following partial structure:

wherein R¹, W, A¹, Q and X¹ are as defined herein, p is 1 or 2, r is 0,1 or 2 and q is 0, 1 or 2. Particular combinations of p, r and q includep=1, r=0, q=0.

R¹⁰ is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkylsulfonyl. Preferably, R¹⁰ ishydrogen.

R¹¹ is hydrogen or C₁-C₆-alkyl. Preferably, R¹¹ is hydrogen.

Alternatively, R⁹, R¹¹ together are C₁-C₄-alkylene.

R¹⁴ is hydrogen or C₁-C₆-alkyl. Preferably, R¹⁴ is hydrogen.

R¹⁵ is hydrogen or C₁-C₆-alkyl. Preferably, R¹⁵ is hydrogen.

Particular embodiments of heterocyclic compounds of the invention resultif

-   A is a 5- or 6-membered heterocyclic ring;-   R is R¹—W-A¹-Q-Y-A²-X¹— or NC-A¹-X¹—;-   R¹ is hydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl,    halogenated C₁-C₆-alkyl, hydroxy-C₁-C₄-alkyl,    C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl,    C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,    C₁-C₆-alkylcarbonylamino-C₁-C₄-alkyl,    C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,    C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,    di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,    C₁-C₆-alkylsulfonylamino-C₁-C₄-alkyl, (optionally substituted    C₆-C₁₂-aryl-C₁-C₆-alkyl)amino-C₁-C₄-alkyl, optionally substituted    C₆-C₁₂-aryl-C₁-C₄-alkyl, optionally substituted    C₃-C₁₂-heterocyclyl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl,    C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, halogenated    C₁-C₆-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl, aminocarbonyl,    C₁-C₆-alkylaminocarbonyl, (halogenated C₁-C₄-alkyl)aminocarbonyl,    C₆-C₁₂-arylaminocarbonyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionally    substituted C₆-C₁₂-aryl, hydroxy, C₁-C₆-alkoxy, halogenated    C₁-C₆-alkoxy, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy,    amino-C₁-C₄-alkoxy, C₁-C₆-alkylamino-C₁-C₄-alkoxy,    di-C₁-C₆-alkylamino-C₁-C₄-alkoxy,    C₁-C₆-alkylcarbonylamino-C₁-C₄-alkoxy,    C₆-C₁₂-arylcarbonylamino-C₁-C₄-alkoxy,    C₁-C₆-alkoxycarbonylamino-C₁-C₄-alkoxy, C₆-C₁₂-aryl-C₁-C₄-alkoxy,    C₁-C₆-alkylsulfonylamino-C₁-C₄-alkoxy, (halogenated    C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,    C₆-C₁₂-arylsulfonylamino-C₁-C₄-alkoxy,    (C₆-C₁₂-aryl-C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,    C₃-C₁₂-heterocyclylsulfonylamino-C₁-C₄-alkoxy,    C₃-C₁₂-heterocyclyl-C₁-C₄-alkoxy, C₆-C₁₂-aryloxy,    C₃-C₁₂-heterocyclyloxy, C₁-C₆-alkylthio, halogenated    C₁-C₆-alkylthio, C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino,    di-C₁-C₆-alkylamino, di-(halogenated C₁-C₆-alkyl)amino,    C₁-C₆-alkylcarbonylamino, (halogenated C₁-C₆-alkyl)carbonylamino,    C₆-C₁₂-arylcarbonylamino, C₁-C₆-alkylsulfonylamino, (halogenated    C₁-C₆-alkyl)sulfonylamino, C₆-C₁₂-arylsulfonylamino or optionally    substituted C₃-C₁₂-heterocyclyl;-   W is —NR⁸— or a bond;-   A¹ is optionally substituted C₁-C₄-alkylene or a bond;-   Q is —S(O)₂—, —C(O)— or a bond;-   Y is —NR⁹— or a bond;-   A² is optionally substituted C₁-C₄-alkylene, C₁-C₄-alkylene-CO—,    —CO—C₁-C₄-alkylene, C₁-C₄-alkylene-O—C₁-C₄-alkylene,    C₁-C₄-alkylene-NR¹⁰—C₁-C₄-alkylene, optionally substituted    C₆-C₁₂-arylene, optionally substituted C₆-C₁₂-heteroarylene or a    bond;-   X¹ is —O—, —NR¹¹—, —S—, optionally substituted C₁-C₄-alkylene or a    bond,-   with the proviso that if Q is a bond, W is —NR⁸— or Y is —NR⁹—;-   R² is hydrogen, halogen, C₁-C₆-alkyl, halogenated C₁-C₄-alkyl,    hydroxy-C₁-C₄-alkyl, —CN, C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionally    substituted C₆-C₁₂-aryl, hydroxy, C₁-C₆-alkoxy, halogenated    C₁-C₆-alkoxy, C₁-C₆-alkoxycarbonyl, C₂-C₆-alkenyloxy,    C₆-C₁₂-aryl-C₁-C₄-alkoxy, C₁-C₆-alkylcarbonyloxy, C₁-C₆-alkylthio,    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, aminosulfonyl, amino,    C₁-C₆-alkylamino, C₂-C₆-alkenylamino, nitro or optionally    substituted C₃-C₁₂-heterocyclyl, or two radicals R² together with    the ring atoms of A to which they are bound form an optionally    substituted 5- or 6-membered ring;-   R³ is hydrogen, halogen, C₁-C₆-alkyl or C₁-C₆-alkoxy, or two    radicals R³ together with the carbon atom to which they are attached    form a carbonyl group;-   R⁴ is hydrogen, C₁-C₆-alkyl, halogenated C₁-C₄-alkyl,    hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl,    CH₂CN, —CHO, C₁-C₄-alkylcarbonyl, (halogenated C₁-C₄-alkyl)carbonyl,    C₁-C₄-alkoxycarbonyl, C₆-C₁₂-arylcarbonyl, C₁-C₆-alkylaminocarbonyl,    C₂-C₆-alkenyl, —C(═NH)NH₂, —C(═NH)NHCN, C₁-C₆-alkylsulfonyl,    C₆-C₁₂-arylsulfonyl, amino or C₃-C₁₂-heterocyclyl;-   X² is —O—, —NR⁶—, —S—, >CR^(12a)R^(12b) or a bond;-   X³ is —O—, —NR⁷—, —S—, >CR^(13a)R^(13b) or a bond;-   R⁵ is optionally substituted C₆-C₁₂-aryl, optionally substituted    C₃-C₁₂-cycloalkyl or optionally substituted C₃-C₁₂-heterocyclyl;-   n is 0, 1, 2;-   R⁶ is hydrogen or C₁-C₆-alkyl;-   R⁷ is hydrogen or C₁-C₆-alkyl;-   R⁸ is hydrogen or C₁-C₆-alkyl;-   R⁹ is hydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl, amino-C₁-C₆-alkyl,    optionally substituted C₆-C₁₂-aryl-C₁-C₄-alkyl; or-   R⁹, R¹¹    -   together are C₁-C₄-alkylene; or-   R⁹ is C₁-C₄-alkylene that is bound to a carbon atom in A² and A² is    C₁-C₄-alkylene or to a carbon atom in X¹ and X¹ is C₁-C₄-alkylene;-   R¹⁰ is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkylsulfonyl;-   R¹¹ is hydrogen or C₁-C₆-alkyl, or-   R⁹, R¹¹    -   together are C₁-C₄-alkylene,-   R^(12a) is hydrogen, optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,    C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl    or hydroxy;-   R^(12b) is hydrogen or C₁-C₆-alkyl, or-   R^(12a), R^(12b)    -   together are carbonyl or optionally substituted C₁-C₄-alkylene,        wherein one —CH₂— of C₁-C₄-alkylene may be replaced by an oxygen        atom or —NR¹⁴—;-   R^(13a) is hydrogen, optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,    C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl    or hydroxy;-   R^(13b) is hydrogen or C₁-C₆-alkyl, or-   R^(13a), R^(13b)    -   together are carbonyl or optionally substituted C₁-C₄-alkylene,        wherein one —CH₂— of C₁-C₄-alkylene may be replaced by an oxygen        atom or —NR¹⁵—;-   R¹⁴ is hydrogen or C₁-C₆-alkyl; and-   R¹⁵ is hydrogen or C₁-C₆-alkyl,-   or if one or more of said variables A, R, R¹, W, A¹, Q, Y, A², X¹,    R², R³, R⁴, X², X³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,    R¹⁵, n are defined more precisely as disclosed herein.

Further particular embodiments of heterocyclic compounds of theinvention result if

-   A is a ring selected from the group consisting of the following 5-    or 6-membered heterocyclic rings:

-   R is R¹—W-A¹-Q-Y-A²-X¹—;-   R¹ is hydrogen, C₁-C₆-alkyl (e.g. methyl; ethyl; n-propyl;    isopropyl, n-butyl, sec-butyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g.    cyclopropylmethyl), halogenated C₁-C₆-alkyl (e.g.    3-fluoroprop-1-yl), C₃-C₁₂-cycloalkyl (e.g. cyclobutyl), optionally    substituted C₆-C₁₂-aryl (e.g. phenyl), or optionally substituted    C₃-C₁₂-heterocyclyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl,    1-methyl-1,2-diazol-4-yl, 1-methyl-1,3-diazol-4-yl);-   W is a bond;-   A¹ is a bond;-   Q is —S(O)₂—, —C(O)— or a bond;-   Y is —NR⁹— or a bond;-   with the proviso that if Q is a bond, Y is —NR⁹—;-   A² is C₁-C₄-alkylene (e.g. methylene; 1,2-ethylene, 1,3-propylene);-   X¹ is a bond;-   R² is hydrogen;-   R³ is hydrogen;-   R⁴ is hydrogen or C₁-C₄-alkoxycarbonyl (e.g. t-butyloxycarbonyl);-   X² is >CR^(12a)R^(12b);-   X³ is a bond;-   R⁵ is optionally substituted phenyl (e.g. phenyl or 4-chlorophenyl);-   R⁹ is hydrogen or C₃-C₁₂-heterocyclyl (e.g. 3-azetidinyl); and-   R^(12a) is hydrogen;-   R^(12b) is hydrogen, or-   R^(12a), R^(12b)    -   together are optionally substituted C₁-C₄-alkylene (e.g.        1,3-propylene).

Further particular embodiments of heterocyclic compounds of theinvention result if

-   A is a ring selected from the group consisting of the following 5-    or 6-membered heterocyclic rings:

-   R is R¹—W-A¹-Q-Y-A²-X¹—;-   R¹ is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl or    n-butyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl),    halogenated C₁-C₆-alkyl (e.g. 3-fluoroprop-1-yl), C₃-C₁₂-cycloalkyl    (e.g. cyclobutyl), optionally substituted C₆-C₁₂-aryl (e.g. phenyl),    or optionally substituted C₃-C₁₂-heterocyclyl (e.g. 3-pyridyl,    1-methyl-1,2-diazol-4-yl or 1-methyl-1,3-diazol-4-yl);-   W is a bond;-   A¹ is a bond;-   Q is —S(O)₂—, —C(O)— or a bond;-   Y is —NR⁹— or a bond;-   with the proviso that if Q is a bond, Y is —NR⁹—;-   A² is C₁-C₄-alkylene (e.g. methylene or 1,2-ethylene);-   X¹ is a bond;-   R² is hydrogen;-   R³ is hydrogen;-   R⁴ is hydrogen or C₁-C₄-alkoxycarbonyl (e.g. t-butyloxycarbonyl);-   X² is >CR^(12a)R^(12b);-   X³ is a bond;-   R⁵ is optionally substituted phenyl (e.g. 4-chlorophenyl);-   R⁹ is hydrogen; and-   R^(12a), R^(12b)    -   together are optionally substituted C₁-C₄-alkylene (e.g.        1,3-propylene).

Particular compounds of the present invention are the heterocycliccompounds disclosed in preparation examples and physiologicallytolerated acid addition salts thereof. These include for eachpreparation example the exemplified compound as well as thecorresponding free base and any other physiologically tolerated acidaddition salts of the free base (if the exemplified compound is a salt),or any physiologically tolerated acid addition salt of the free base (ifthe exemplified compound is a free base). These further includeenantiomers, diastereomers, tautomers and any other isomeric forms ofsaid compounds, be they explicitly or implicitly disclosed.

The compounds of the formula (I) can be prepared by analogy to methodswhich are well known in the art. Suitable methods for the preparation ofcompounds of formula (I) is outlined in the following schemes.

The processes depicted in schemes 1 and 2 are useful for obtaining2-substituted piperidin-3-ones which then can be converted to2-substituted 4-((dimethyl)methylene)-3-oxopiperidines according to theprocess depicted in scheme 3.

As shown in scheme 1, the compound of general formula 1 readilyundergoes enamine alkylation to give the compound of general formula 2.

As shown in scheme 2, the compound of general formula 3 readilyundergoes acid catalyzed condensation with the compound of generalformula 4 in the presence of ammonium acetate to give the compound ofgeneral formula 5. The compound of general formula 5 can be furtherfunctionalized using standard transformations (e.g. amid reduction, Nefreaction) to yield the compound of general formula 2.

As shown in scheme 3, the compound of general formula 2 readilyundergoes condensation with dimethylformamide dimethyl acetal to givethe compound of general formula 6.

The process depicted in scheme 4 is useful for obtaining4,5-dihydro-pyrazolo[3,4-c]pyridines of the present invention.

As shown in scheme 4, the intermediate of general formula 6 can bereacted with various nucleophiles of general formula H₂N—NH—R in analcoholic solvent, preferably methanol or ethanol, at a temperature ofabout 20° to 80° C. to obtain the compounds of general formulae 7 and 8.In case of monosubstituted hydrazines regioisomeric products are formed.

The process depicted in scheme 5 is useful for obtaining4,5,6,7-tetrahydroisoxazolo[3,4-c]pyridines of the present invention.

As shown in scheme 5, the intermediate of general formula 6 can bereacted with hydroxylamine under appropriate conditions to obtaincompound of the general formula 9.

The process depicted in scheme 6 is useful for obtaining5,6,7,8-tetrahydro-1,7-naphthyridines of the present invention.

As shown in scheme 6, the condensation of compound of general formula 6with the reagent of general formula 10 and ammonia acetate in refluxingacetic acid gives the compound of general formula 11. R² is —CO₂Me,—CO₂Et, —CN, NO₂, or the like.

The process depicted in scheme 7 is useful for obtaining5,6,7,8-tetrahydro[3,4-d]pyrimidines of the present invention.

As shown in scheme 7, the cyclocondensation of the intermediate ofgeneral formula 6 with the 1,3-nucleophiles of general formula 12 in thepresence of suitable organic or inorganic bases such as KOH, NaOH,NaHCO₃, sodium ethoxide, sodium methoxide, triethyl amine anddiisopropyl ethyl amine in an alcoholic solvent, preferably ethanol ormethanol, at a temperature of about 20° to 80° C. yields the compound ofgeneral formula 13.

The process depicted in scheme 8 is useful for obtaining4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines and4,5,6,7-tetrahydrothiazolo[4,5-c]pyridines of the present invention.

As shown in scheme 8, the reaction of the compound of general formula 2with standard agents, e.g. hydroxyl(tosyloxy)iodobenzene, gives thecompound of formula 14 wherein Lg is a leaving group (e.g. tosylate,bromide, etc.). Reaction of the compound of general formula 14 with1,3-nucleophiles under appropriate conditions yields the compound ofgeneral formula 15. Y is S or N.

The process depicted in scheme 9 is useful for obtaining4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridines of the present invention.

As shown in scheme 9, the reaction of the intermediate of generalformula 2 with an optionally substituted aldehyde in presence of asuitable base such as alkyl lithium, LDA, LHMDS gives the intermediateof general formula 16. The intermediate of general formula 16 can becyclised to the derivate of general formula 17 under suitable acidicconditions. The derivate of general formula 17 can be furtherfunctionalized to give the optionally substituted compound of generalformula 18 using conventional chemical transformations.

The process depicted in scheme 10 is useful for obtaining4,5,6,7-tetrahydrooxazolo[5,4-c]pyridines and4,5,6,7-tetrahydrothiazolo[5,4-c]pyridines of the present invention.

As shown in scheme 10, the reaction of intermediate of general formula19 with an optionally substituted acid in presence of a standardcoupling reagent (e.g. DCC, EDC, HATU, etc.) yields the intermediate ofgeneral formula 20. The intermediate of general formula 20 can becyclised to the derivate of general formula 21 under suitable conditionsusing standard methodology (Lawesson's reagent, triphosgen). X is O orS.

The process depicted in scheme 11 is useful for obtaining5,6,7,8-tetrahydropyrido[4,3-b]pyrazines of the present invention.

As shown in scheme 11, the reaction of the naphthyridine of generalformula 22 with an optionally substituted stannane in the presence ofethylchloroformate gives the dihydronaphthyridine of general formula 23.Reduction of the olefin using conventional hydrogenation methods andremoval of the protecting group gives the compound of general formula 24(cf. Tetrahedron 2000, 41, 8053). W is CH and Z is N, or W is N and Z isCH.

The process depicted in scheme 12 is useful for obtaining4,5,6,7-tetrahydrothieno[2,3-c]pyridines of the present invention.

As shown in the scheme 12, the reaction of ketone of general formula 25with malonic acid dinitrile in the presence of sulfur an a suitable basegives thiophenes of general formula 26. Conversion of the amino group byconventional reaction methods leads to thiophens of general formula 27.The thiophens of general formula 27 can be further functionalized togive optionally substituted compounds using conventional chemicaltransformations.

The processes depicted in schemes 13 and 14 are useful for obtaining5,6,7,8-tetrahydrothiazolo[4,5-c]pyrazines of the present invention.

As shown in scheme 13 the synthesis of scaffold of general structure 33can achieved starting from commercial available3-oxo-piperidine-1-carboxylic acid tert-butyl ester. 28 can be condensedwith pyrrolidine by heating in toluene to yield the enamine 29. Thecrude enamine 29 can be reacted with various benzyl bromides to yieldthe compounds of general structure 30. Scaffold 30 can be brominated bysimple stirring in chloroform in the presence of bromine to yield thedesired product 31. The compounds 31 can be used directly in the nextstep. Condensation with suitable thioamides, followed by acidicdeprotection gives access to scaffold 33.

Scaffold 33 can easily be modified following the reaction outlined inscheme 14. Standard procedures like acylation or reductive aminationusing standard reaction protocols leads to scaffold of general structure34 and 35.

In schemes 1 to 14, the variables R, R², R⁴, X², X³ and R⁵ areas definedherein or represent a group that can be converted into the desiredgroup, as shown in the following schemes 15 to 17.

As shown in the scheme 15, the reaction of compounds of the generalformula 36 with a suitable substituted nucleophile gives the compound ofgeneral formula 37.

As shown in the scheme 16, compounds of the general formula 38 giveunder standard Pd-cross coupling condition compounds of the generalformula 38 and 40. Nitriles of general formula 40 give compounds ofgeneral formula 41 using standard reduction methods.

As shown in scheme 17, intermediates of general structure 44 givecompounds of general structure 46 via introduction of a leaving group(halogen, tosylate, etc.) followed by nucleophilic replacement.Reduction of intermediates of general structure 46 and 48 givescompounds of general structure 47. The derivate of general formula 47can be further functionalized to give the optionally substitutedcompound of general formula 49 using conventional chemicaltransformations.

The acid addition salts of the heterocyclic compounds of formula (I) areprepared in a customary manner by mixing the free base with acorresponding acid, optionally in solution in an organic solvent, forexample a lower alcohol, such as methanol, ethanol or propanol, anether, such as methyl tert-butyl ether or diisopropyl ether, a ketone,such as acetone or methyl ethyl ketone, or an ester, such as ethylacetate.

The compounds of the formula (I) are capable of inhibiting the activityof glycine transporter, in particular glycine transporter 1 (GlyT1).

The utility of the compounds in accordance with the present invention asinhibiting the glycine transporter activity, in particular GlyT1activity, may be demonstrated by methodology known in the art. Forinstance, human GlyT1c expressing recombinant hGlyT1c_5_CHO cells can beused for measuring glycine uptake and its inhibition (IC₅₀) by acompound of formula (I).

Amongst the compounds of the formula (I) those are preferred whichachieve effective inhibition at low concentrations. In particular,compounds of the formula (I) are preferred which inhibit glycinetransporter 1 (GlyT1) at a level of IC₅₀<1 μMol, more preferably at alevel of IC₅₀<0.5 μMol, particularly preferably at a level of IC₅₀<0.2μMol and most preferably at a level of IC₅₀<0.1 μMol.

The compounds of the formula (I) according to the present invention arethus useful as pharmaceuticals.

The present invention therefore also relates to pharmaceuticalcompositions which comprise an inert carrier and a compound of theformula (I).

The present invention also relates to the use of the compounds of theformula (I) in the manufacture of a medicament for inhibiting theglycine transporter GlyT1, and to corresponding methods of inhibitingthe glycine transporter GlyT1.

The NMDA receptor is central to a wide range of CNS processes, and itsrole in a variety of diseases in humans or other species has beendescribed. GlyT1 inhibitors slow the removal of glycine from thesynapse, causing the level of synaptic glycine to rise. This in turnincreases the occupancy of the glycine binding site on the NMDAreceptor, which increases activation of the NMDA receptor followingglutamate release from the presynaptic terminal. Glycine transportinhibitors and in particular inhibitors of the glycine trans-porterGlyT1 are thus known to be useful in treating a variety of neurologicand psychiatric disorders. Further, glycine A receptors play a role in avariety of diseases in humans or other species. Increasing extracellularglycine concentrations by inhibiting glycine trans-port may enhance theactivity of glycine A receptors. Glycine transport inhibitors and inparticular inhibitors of the glycine transporter GlyT1 are thus usefulin treating a variety of neurologic and psychiatric disorders.

The present invention thus further relates to the use of the compoundsof the formula (I) for the manufacture of a medicament for treating aneurologic or psychiatric disorder, and to corresponding methods oftreating said disorders.

According to a particular embodiment, the disorder is associated withglycinergic or glutamatergic neurotransmission dysfunction.

According to a further particular embodiment, the disorder is one ormore of the following conditions or diseases: schizophrenia or apsychotic disorder including schizophrenia (paranoid, disorganized,catatonic or undifferentiated), schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition and substance-induced psychotic disorder, including both thepositive and the negative symptoms of schizophrenia and other psychoses;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, multi-infarct dementia, trauma, vascular problems orstroke, HIV disease, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeldt-Jacob disease, perinatal hypoxia, other generalmedical conditions or substance abuse); delirium, amnestic disorders orcognitive impairment including age related cognitive decline; anxietydisorders including acute stress disorder, agoraphobia, generalizedanxiety disorder, obsessive-compulsive disorder, panic attack, panicdisorder, post-traumatic stress disorder, separation anxiety disorder,social phobia, specific phobia, substance-induced anxiety disorder andanxiety due to a general medical condition; substance-related disordersand addictive behaviors (including substance-induced delirium,persisting dementia, persisting amnestic disorder, psychotic disorder oranxiety disorder; tolerance, dependence or withdrawal from substancesincluding alcohol, amphetamines, cannabis, cocaine, hallucinogens,inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics oranxiolytics); obesity, bulimia nervosa and compulsive eating disorders;bipolar disorders, mood disorders including depressive disorders;depression including unipolar depression, seasonal depression andpost-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), mood disorders due to a general medicalcondition, and substance-induced mood disorders; learning disorders,pervasive developmental disorder including autistic disorder, attentiondeficit disorders including attention-deficit hyperactivity disorder(ADHD) and conduct disorder; movement disorders, including akinesias andakinetic-rigid syndromes (including Parkinson's disease, drug-inducedparkinsonism, postencephalitic parkinsonism, progressive supranuclearpalsy, multiple system atrophy, corticobasal degeneration,parkinsonism-ALS dementia complex and basal ganglia calcification),medication-induced parkinsonism (such as neuroleptic-inducedparkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acutedystonia, neuroleptic-induced acute akathisia, neuroleptic-inducedtardive dyskinesia and medication-induced postural tremor), Gilles de laTourette's syndrome, epilepsy, muscular spasms and disorders associatedwith muscular spasticity or weakness including tremors; dyskinesias[including tremor (such as rest tremor, postural tremor and intentiontremor), chorea (such as Sydenham's chorea, Huntington's disease, benignhereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-inducedchorea and hemiballism), myoclonus (including generalised myoclonus andfocal myoclonus), tics (including simple tics, complex tics andsymptomatic tics), and dystonia (including generalised dystonia such asiodiopathic dystonia, drug-induced dystonia, symptomatic dystonia andparoxymal dystonia, and focal dystonia such as blepharospasm,oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis,axial dystonia, dystonic writers cramp and hemiplegic dystonia)];urinary incontinence; neuronal damage including ocular damage,retinopathy or macular degeneration of the eye, tinnitus, hearingimpairment and loss, and brain edema; emesis; and sleep disordersincluding insomnia and narcolepsy.

According to a further particular embodiment, the disorder is pain, inparticular chronic pain and especially neuropathic pain.

Pain can be classified as acute and chronic pain. Acute pain and chronicpain differ in their etiology, pathophysiology, diagnosis and treatment.

Acute pain, which occurs following tissue injury, is self-limiting,serves as an alert to ongoing tissue damage and following tissue repairit will usually subside. There are minimal psychological symptomsassociated with acute pain apart from mild anxiety. Acute pain isnociceptive in nature and occurs following chemical, mechanical andthermal stimulation of A-delta and C-polymodal pain receptors.

Chronic pain, on the other hand, serves no protective biologicalfunction. Rather than being the symptom of tissue damage it is a diseasein its own right. Chronic pain is unrelenting and not self-limiting andcan persist for years, perhaps decades after the initial injury. Chronicpain can be refractory to multiple treatment regimes. Psychologicalsymptoms associated with chronic pain include chronic anxiety, fear,depression, sleeplessness and impairment of social interaction. Chronicnon-malignant pain is predominantly neuropathic in nature and involvesdamage to either the peripheral or central nervous systems.

Acute pain and chronic pain are caused by different neuro-physiologicalprocesses and therefore tend to respond to different types oftreatments. Acute pain can be somatic or visceral in nature. Somaticpain tends to be a well localised, constant pain and is described assharp, aching, throbbing or gnawing. Visceral pain, on the other hand,tends to be vague in distribution, paroxysmal in nature and is usuallydescribed as deep, aching, squeezing or colicky in nature. Examples ofacute pain include post-operative pain, pain associated with trauma andthe pain of arthritis. Acute pain usually responds to treatment withopioids or non-steroidal anti-inflammatory drugs.

Chronic pain, in contrast to acute pain, is described as burning,electric, tingling and shooting in nature. It can be continuous orparoxysmal in presentation. The hallmarks of chronic pain are chronicallodynia and hyperalgesia. Allodynia is pain resulting from a stimulusthat normally does not ellicit a painful response, such as a lighttouch. Hyperalgesia is an increased sensitivity to normally painfulstimuli. Primary hyperalgesia occurs immediately within the area of theinjury. Secondary hyperalgesia occurs in the undamaged area surroundingthe injury. Examples of chronic pain include complex regional painsyndrome, pain arising from peripheral neuropathies, post-operativepain, chronic fatigue syndrome pain, tension-type headache, pain arisingfrom mechanical nerve injury and severe pain associated with diseasessuch as cancer, metabolic disease, neurotropic viral disease,neurotoxicity, inflammation, multiple sclerosis or any pain arising as aconsequence of or associated with stress or depressive illness.

Although opioids are cheap and effective, serious and potentiallylife-threatening side effects occur with their use, most notablyrespiratory depression and muscle rigidity. In addition the doses ofopioids which can be administered are limited by nausea, emesis,constipation, pruritis and urinary retention, often resulting inpatients electing to receive suboptimal pain control rather than sufferthese distressing side-effects. Furthermore, these side-effects oftenresult in patients requiring extended hospitalisation. Opioids arehighly addictive and are scheduled drugs in many territories.

The compounds of formula (I) are particularly useful in the treatment ofschizophrenia, bipolar disorder, depression including unipolardepression, seasonal depression and postpartum depression, premenstrualsyndrome (PMS) and premenstrual dysphoric disorder (PDD), learningdisorders, pervasive developmental disorder including autistic disorder,attention deficit disorders including Attention-Deficit/HyperactivityDisorder, tic disorders including Tourette's disorder, anxiety disordersincluding phobia and post traumatic stress disorder, cognitive disordersassociated with dementia, AIDS dementia, Alzheimer's, Parkinson's,Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus andhearing impairment and loss are of particular importance.

Particular cognitive disorders are dementia, delirium, amnesticdisorders and cognitive impairment including age-related cognitivedecline.

Particular anxiety disorders are generalized anxiety disorder,obsessive-compulsive disorder and panic attack.

Particular schizophrenia or psychosis pathologies are paranoid,disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder.

Particular neurologic disorders that can be treated with the compoundsof the formula (I) include in particular a cognitive disorder such asdementia, cognitive impairment, attention deficit hyperactivitydisorder.

Particular psychiatric disorders that can be treated with the compoundsof the formula (I) include in particular an anxiety disorder, a mooddisorder such as depression or a bipolar disorder, schizophrenia, apsychotic disorder.

Within the context of the treatment, the use according to the inventionof the compounds of the formula (I) involves a method. In this method,an effective quantity of one or more compounds or the formula (I), as arule formulated in accordance with pharmaceutical and veterinarypractice, is administered to the individual to be treated, preferably amammal, in particular a human being. Whether such a treatment isindicated, and in which form it is to take place, depends on theindividual case and is subject to medical assessment (diagnosis) whichtakes into consideration signs, symptoms and/or malfunctions which arepresent, the risks of developing particular signs, symptoms and/ormalfunctions, and other factors.

As a rule, the treatment is effected by means of single or repeateddaily administration, where appropriate together, or alternating, withother drugs or drug-containing preparations.

The invention also relates to the manufacture of pharmaceuticalcompositions for treating an individual, preferably a mammal, inparticular a human being. Thus, the compounds of the formula (I) arecustomarily administered in the form of pharmaceutical compositionswhich comprise an inert carrier (e.g. a pharmaceutically acceptableexcipient) together with at least one compound according to theinvention and, where appropriate, other drugs. These compositions can,for example, be administered orally, rectally, transdermally,subcutaneously, intravenously, intramuscularly or intranasally.

Examples of suitable pharmaceutical formulations are solid medicinalforms, such as powders, granules, tablets, in particular film tablets,lozenges, sachets, cachets, sugar-coated tablets, capsules, such as hardgelatin capsules and soft gelatin capsules, suppositories or vaginalmedicinal forms, semisolid medicinal forms, such as ointments, creams,hydrogels, pastes or plasters, and also liquid medicinal forms, such assolutions, emulsions, in particular oil-in-water emulsions, suspensions,for example lotions, injection preparations and infusion preparations,and eyedrops and eardrops. Implanted release devices can also be usedfor administering inhibitors according to the invention. In addition, itis also possible to use liposomes or microspheres.

When producing the compositions, the compounds according to theinvention are optionally mixed or diluted with one or more carriers(excipients). Carriers (excipients) can be solid, semisolid or liquidmaterials which serve as vehicles, carriers or medium for the activecompound.

Suitable carriers (excipients) are listed in the specialist medicinalmonographs. In addition, the formulations can comprise pharmaceuticallyacceptable auxiliary substances, such as wetting agents; emulsifying andsuspending agents; preservatives; antioxidants; antiirritants; chelatingagents; coating auxiliaries; emulsion stabilizers; film formers; gelformers; odor masking agents; taste corrigents; resin; hydrocolloids;solvents; solubilizers; neutralizing agents; diffusion accelerators;pigments; quaternary ammonium compounds; refatting and overfattingagents; raw materials for ointments, creams or oils; siliconederivatives; spreading auxiliaries; stabilizers; sterilants; suppositorybases; tablet auxiliaries, such as binders, fillers, glidants,disintegrants or coatings; propellants; drying agents; opacifiers;thickeners; waxes; plasticizers and white mineral oils. A formulation inthis regard is based on specialist knowledge as described, for example,in Fiedler, H. P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik andangrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy,cosmetics and related fields], 4^(th) edition, Aulendorf:ECV-Editio-Cantor-Verlag, 1996.

The compounds of formula (I) may also be suitable for combination withother therapeutic agents.

Thus, the present invention also provides:

i) a combination comprising a compound of formula (I) with one or morefurther therapeutic agents;ii) a pharmaceutical composition comprising a combination product asdefined in i) above and at least one carrier, diluent or excipient;iii) the use of a combination as defined in i) above in the manufactureof a medicament for treating or preventing a disorder, disease orcondition as defined herein;iv) a combination as defined in i) above for use in treating orpreventing a disorder, disease or condition as defined herein;v) a kit-of-parts for use in the treatment of a disorder, disease orcondition as defined herein, comprising a first dosage form comprising acompound of formula (I) and one or more further dosage forms eachcomprising one or more further therapeutic agents for simultaneoustherapeutic administration,vi) a combination as defined in i) above for use in therapy;vii) a method of treatment or prevention of a disorder, disease orcondition as defined herein comprising administering an effective amountof a combination as defined in i) above;viii) a combination as defined in i) above for treating or preventing adisorder, disease or condition as defined herein.

The combination therapies of the invention may be administeredadjunctively. By adjunctive administration is meant the coterminous oroverlapping administration of each of the components in the form ofseparate pharmaceutical compositions or devices. This regime oftherapeutic administration of two or more therapeutic agents is referredto generally by those skilled in the art and herein as adjunctivetherapeutic administration; it is also known as add-on therapeuticadministration. Any and all treatment regimes in which a patientreceives separate but coterminous or overlapping therapeuticadministration of the compounds of formula (I) and at least one furthertherapeutic agent are within the scope of the current invention. In oneembodiment of adjunctive therapeutic administration as described herein,a patient is typically stabilised on a therapeutic administration of oneor more of the components for a period of time and then receivesadministration of another component.

The combination therapies of the invention may also be administeredsimultaneously. By simultaneous administration is meant a treatmentregime wherein the individual components are administered together,either in the form of a single pharmaceutical composition or devicecomprising or containing both components, or as separate compositions ordevices, each comprising one of the components, administeredsimultaneously. Such combinations of the separate individual componentsfor simultaneous combination may be provided in the form of akit-of-parts.

In a further aspect, the invention provides a method of treatment of apsychotic disorder by adjunctive therapeutic administration of compoundsof formula (I) to a patient receiving therapeutic administration of atleast one antipsychotic agent. In a further aspect, the inventionprovides the use of compounds of formula (I) in the manufacture of amedicament for adjunctive therapeutic administration for the treatmentof a psychotic disorder in a patient receiving therapeuticadministration of at least one antipsychotic agent. The inventionfurther provides compounds of formula (I) for use for adjunctivetherapeutic administration for the treatment of a psychotic disorder ina patient receiving therapeutic administration of at least oneantipsychotic agent.

In a further aspect, the invention provides a method of treatment of apsychotic disorder by adjunctive therapeutic administration of at leastone antipsychotic agent to a patient receiving therapeuticadministration of compounds of formula (I). In a further aspect, theinvention provides the use of at least one antipsychotic agent in themanufacture of a medicament for adjunctive therapeutic administrationfor the treatment of a psychotic disorder in a patient receivingtherapeutic administration of compounds of formula (I). The inventionfurther provides at least one antipsychotic agent for adjunctivetherapeutic administration for the treatment of a psychotic disorder ina patient receiving therapeutic administration of compounds of formula(I).

In a further aspect, the invention provides a method of treatment of apsychotic disorder by simultaneous therapeutic administration ofcompounds of formula (I) in combination with at least one antipsychoticagent. The invention further provides the use of a combination ofcompounds of formula (I) and at least one antipsychotic agent in themanufacture of a medicament for simultaneous therapeutic administrationin the treatment of a psychotic disorder. The invention further providesa combination of compounds of formula (I) and at least one antipsychoticagent for simultaneous therapeutic administration in the treatment of apsychotic disorder. The invention further provides the use of compoundsof formula (I) in the manufacture of a medicament for simultaneoustherapeutic administration with at least one antipsychotic agent in thetreatment of a psychotic disorder. The invention further providescompounds of formula (I) for use for simultaneous therapeuticadministration with at least one antipsychotic agent in the treatment ofa psychotic disorder. The invention further provides the use of at leastone antipsychotic agent in the manufacture of a medicament forsimultaneous therapeutic administration with compounds of formula (I) inthe treatment of a psychotic disorder. The invention further provides atleast one antipsychotic agent for simultaneous therapeuticadministration with compounds of formula (I) in the treatment of apsychotic disorder.

In further aspects, the invention provides a method of treatment of apsychotic disorder by simultaneous therapeutic administration of apharmaceutical composition comprising compounds of formula (I) and atleast one mood stabilising or antimanic agent, a pharmaceuticalcomposition comprising compounds of formula (I) and at least one moodstabilising or antimanic agent, the use of a pharmaceutical compositioncomprising compounds of formula (I) and at least one mood stabilising orantimanic agent in the manufacture of a medicament for the treatment ofa psychotic disorder, and a pharmaceutical composition comprisingcompounds of formula (I) and at least one mood stabilising or antimanicagent for use in the treatment of a psychotic disorder.

Antipsychotic agents include both typical and atypical antipsychoticdrugs. Examples of antipsychotic drugs that are useful in the presentinvention include, but are not limited to: butyrophenones, such ashaloperidol, pimozide, and droperidol; phenothiazines, such aschlorpromazine, thioridazine, mesoridazine, trifluoperazine,perphenazine, fluphenazine, thiflupromazine, prochlorperazine, andacetophenazine; thioxanthenes, such as thiothixene and chlorprothixene;thienobenzodiazepines; dibenzodiazepines; benzisoxazoles;dibenzothiazepines; imidazolidinones; benziso-thiazolyl-piperazines;triazine such as lamotrigine; dibenzoxazepines, such as loxapine;dihydroindolones, such as molindone; aripiprazole; and derivativesthereof that have antipsychotic activity.

Examples of tradenames and suppliers of selected antipsychotic drugs areas follows: clozapine (available under the tradename CLOZARIL®, fromMylan, Zenith Goldline, UDL, Novartis); olanzapine (available under thetradename ZYPREX®, from Lilly); ziprasidone (available under thetradename GEODON®, from Pfizer); risperidone (available under thetradename RISPERDAL®, from Janssen); quetiapine fumarate (availableunder the tradename SEROQUEL®, from AstraZeneca); haloperidol (availableunder the tradename HALDOL®, from Ortho-McNeil); chlorpromazine(available under the tradename THORAZINE®, from SmithKline Beecham(GSK)); fluphenazine (available under the tradename PROLIXIN®, fromApothecon, Copley, Schering, Teva, and American Pharmaceutical Partners,Pasadena); thiothixene (available under the tradename NAVANE®, fromPfizer); trifluoperazine(10-[3-(4-methyl-1-piperazinyl)propyl]-2-(trifluoromethyl)phenothiazinedihydrochloride, available under the tradename STELAZINE®, from SmithKlein Beckman); perphenazine (available under the tradename TRILAFON®;from Schering); thioridazine (available under the tradename MELLARIL®;from Novartis, Roxane, HiTech, Teva, and Alpharma); molindone (availableunder the tradename MOBAN®, from Endo); and loxapine (available underthe tradename LOXITANE (D; from Watson). Furthermore, benperidol(Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®) may be used.Other antipsychotic drugs include promazine (available under thetradename SPARINE®), triflurpromazine (available under the tradenameVESPRIN®), chlorprothixene (available under the tradename TARACTAN®),droperidol (available under the tradename INAPSINE®), acetophenazine(available under the tradename TINDAL®), prochlorperazine (availableunder the tradename COMPAZINE®), methotrimeprazine (available under thetradename NOZINAN®), pipotiazine (available under the tradenamePIPOTRIL®), ziprasidone, and hoperidone.

In a further aspect, the invention provides a method of treatment of aneurodegenerative disorder such as Alzheimer Disease by adjunctivetherapeutic administration of compounds of formula (I) to a patientreceiving therapeutic administration of at least one agent suitable forthe treatment of a neurodegenerative disorder such as Alzheimer Disease.In a further aspect, the invention provides the use of compounds offormula (I) in the manufacture of a medicament for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides compounds of formula (I) for use for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease.

In a further aspect, the invention provides a method of treatment of aneurodegenerative disorder such as Alzheimer Disease by adjunctivetherapeutic administration of at least one agent suitable for thetreatment of a neurodegenerative disorder such as Alzheimer Disease to apatient receiving therapeutic administration of compounds of formula(I). In a further aspect, the invention provides the use of at least oneagent suitable for the treatment of a neurodegenerative disorder such asAlzheimer Disease in the manufacture of a medicament for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of compounds of formula (I). The invention furtherprovides at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of compounds of formula (I).

In a further aspect, the invention provides a method of treatment of aneurodegenerative disorder such as Alzheimer Disease by simultaneoustherapeutic administration of compounds of formula (I) in combinationwith at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides the use of a combination of compounds of formula (I)and at least one agent suitable for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in the manufacture of a medicamentfor simultaneous therapeutic administration in the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides a combination of compounds of formula (I) and at leastone agent suitable for the treatment of a neurodegenerative disordersuch as Alzheimer Disease for simultaneous therapeutic administration inthe treatment of a neurodegenerative disorder such as Alzheimer Disease.The invention further provides the use of compounds of formula (I) inthe manufacture of a medicament for simultaneous therapeuticadministration with at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease in the treatment ofa neurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides compounds of formula (I) for use for simultaneoustherapeutic administration with at least one agent suitable for thetreatment of a neurodegenerative disorder such as Alzheimer Disease inthe treatment of a neurodegenerative disorder such as Alzheimer Disease.The invention further provides the use of at least one agent suitablefor the treatment of a neurodegenerative disorder such as AlzheimerDisease in the manufacture of a medicament for simultaneous therapeuticadministration with compounds of formula (I) in the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease for simultaneoustherapeutic administration with compounds of formula (I) in thetreatment of a neurodegenerative disorder such as Alzheimer Disease.

Examples of agents suitable for the treatment of a neurodegenerativedisorder such as Alzheimer Disease that are useful in the presentinvention include, but are not limited to: cholinesterase inhibitors,agents targeting nicotinic or muscarinic acethylcholine receptors, NMDAreceptors, amyloid formation, mitochondrial dysfunctions, diseaseassociated calpain activity, neuroinflamation, tumor necrosis factorreceptors, NF-kappaB, peroxisome proliferator activator receptor gamma,Apolipoprotein E variant 4 (ApoE4), disease-associated increase of theHPA axis, epileptic discharges, vascular dysfunction, vascular riskfactors, and oxidative stress.

Suitable cholinesterase inhibitors which may be used in combination withthe compounds of the inventions include for example tacrine, donepezil,galantamine and rivastigmine.

Suitable NMDA receptors targeting agents which may be used incombination with the compounds of the inventions include for examplememantine.

Suitable agents affecting increased HPA axis activity which may be usedin combination with the compounds of the inventions include for exampleCRF1 antagonists or V1 b antagonists.

In a further aspect therefore, the invention provides a method oftreatment of pain by adjunctive therapeutic administration of compoundsof formula (I) to a patient receiving therapeutic administration of atleast one agent suitable for the treatment of pain. In a further aspect,the invention provides the use of compounds of formula (I) in themanufacture of a medicament for adjunctive therapeutic administrationfor the treatment of pain in a patient receiving therapeuticadministration of at least one agent suitable for the treatment of pain.The invention further provides compounds of formula (I) for use foradjunctive therapeutic administration for the treatment of pain in apatient receiving therapeutic administration of at least one agentsuitable for the treatment of pain.

In a further aspect, the invention provides a method of treatment ofpain by adjunctive therapeutic administration of at least one agentsuitable for the treatment of pain to a patient receiving therapeuticadministration of compounds of formula (I). In a further aspect, theinvention provides the use of at least one agent suitable for thetreatment of pain in the manufacture of a medicament for adjunctivetherapeutic administration for the treatment of pain in a patientreceiving therapeutic administration of compounds of formula (I). Theinvention further provides at least one agent suitable for the treatmentof pain for adjunctive therapeutic administration for the treatment ofpain in a patient receiving therapeutic administration of compounds offormula (I).

In a further aspect, the invention provides a method of treatment ofpain by simultaneous therapeutic administration of compounds of formula(I) in combination with at least one agent suitable for the treatment ofpain. The invention further provides the use of a combination ofcompounds of formula (I) and at least one agent suitable for thetreatment of pain in the manufacture of a medicament for simultaneoustherapeutic administration in the treatment of pain. The inventionfurther provides a combination of compounds of formula (I) and at leastone agent suitable for the treatment of pain for simultaneoustherapeutic administration in the treatment of pain. The inventionfurther provides the use of compounds of formula (I) in the manufactureof a medicament for simultaneous therapeutic administration with atleast one agent suitable for the treatment of pain in the treatment ofpain. The invention further provides compounds of formula (I) for usefor simultaneous therapeutic administration with at least one agentsuitable for the treatment of pain in the treatment of pain. Theinvention further provides the use of at least one agent suitable forthe treatment of pain in the manufacture of a medicament forsimultaneous therapeutic administration with compounds of formula (I) inthe treatment of pain. The invention further provides at least one agentsuitable for the treatment of pain for simultaneous therapeuticadministration with compounds of formula (I) in the treatment of pain.

Examples of agents suitable for the treatment of pain that are useful inthe present invention include, but are not limited to: NSAIDs(Nonsteroidal Antiinflammatory Drugs), anti-convulsant drugs such ascarbamazepine and gabapentin, sodium channel blockers, anti-depressantdrugs, cannabinoids and local anaesthetics.

Suitable agents used in combination with the compounds of the inventionsinclude for example celecoxib, etoricoxib, lumiracoxib, paracetamol,tramadol, methadone, venlafaxine, imipramine, duloxetine, bupropion,gabapentin, pregabalin, lamotrigine, fentanyl, parecoxib, nefopam,remifentanil, pethidine, diclofenac, rofecoxib, nalbuphine, sufentanil,pethidine, diamorphine and butorphanol.

It will be appreciated by those skilled in the art that the compoundsaccording to the invention may advantageously be used in conjunctionwith one or more other therapeutic agents, for instance, antidepressantagents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists,selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptakeinhibitors (SNRI), tricyclic antidepressants, dopaminergicantidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B antagonists,5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsantagents, as well as cognitive enhancers.

Suitable 5HT3 antagonists which may be used in combination of thecompounds of the inventions include for example ondansetron,granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbine,metoclopramide.

Suitable SSRIs which may be used in combination with the compounds ofthe invention include fluoxetine, citalopram, femoxetine, fluvoxamine,paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRIs which may be used in combination with the compounds ofthe invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination witha compound of the invention include imipramine, amitriptiline,chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combinationwith a compound of the invention include bupropion and amineptine.

Suitable anticonvulsant agents which may be used in combination of thecompounds of the invention include for example divalproex, carbamazepineand diazepam.

The following examples serve to explain the invention without limitingit.

The compounds were characterized by mass spectrometry, generallyrecorded via HPLC-MS in a fast gradient on C18-material(electrospray-ionisation (ESI) mode).

PREPARATION EXAMPLES Intermediates Intermediate 11-(4-Chlorophenyl)cyclobutanecarbaldehyde

To a solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (36.2 g; 190mmol) in toluene (500 ml) was added DiBAL-H (230 ml; 1 M; 1.2 eq) at−78° C. The mixture was stirred at −78° C. for 2 h. The cool mixture wasadded under vigorous stirring to HCl (2 M; 400 ml). The organic phasewas separated, washed with HCl (2 M), water, brine, dried over MgSO₄ andevaporated. The crude product (34 g; 175 mmol; 92%) was used withoutfurther purification.

Intermediate 2 6-(1-(4-Chlorophenyl)cyclobutyl)-5-nitropiperidin-2-one

A mixture of intermediate 1 (30 g; 154 mmol), methyl 4-nitrobutyrate (1eq; 154 mmol; 19 ml) and ammonium acetate (2 eq; 300 mmol; 24 g) inethanol (65 ml) was heated in the micro wave for 2 h. The mixture wasdiluted with EtOAc and washed with saturated Na—HCO₃ solution, water andbrine, dried over MgSO₄ and evaporated. The residue was rinsed withn-heptan to yield a pale yellow solid. The product (29 g; 64%) was usedwithout further purification.

ESI-MS [M+H⁺]=309 Calculated for C₁₅H₁₇ClN₂O₃=308

Intermediate 3 2-(1-(4-Chlorophenyl)cyclobutyl)-3-nitropiperidine

A mixture of intermediate 2 (30 g; 97 mmol) and boran dimethylsulfidcomplex (1.6 eq; 15 ml) in THF was heated under reflux for 48 h. Thereaction was cooled to room temperature and quenched by addition ofaqueous NaOH solution. The phases were separated and the organic layerwas washed with aqueous NaOH, water and brine, dried over MgSO₄ andevaporated. The crude product (25 g; 87%) was used without furtherpurification.

ESI-MS [M+H⁺]=295 Calculated for C₁₃H₁₃ClN₂O₂=294

Intermediate 4 2-(1-(4-Chlorophenyl)cyclobutyl)piperidin-3-one

A mixture of intermediate 3 (10 g; 35 mmol) and KOH (15 g; 280 mmol; 8eq) in ethanol/water (100 ml; 1/1) was heated for 30 min at 40° C. Tothis solution was added a solution of TiCl₃ (10% in HCl; 170 mmol; 5 eq)and ammonium acetate (40 g; 500 mmol; 15 eq) in water at 40° C. Themixture was stirred for additional 2 h at 40° C. The cooled mixture waspartitioned between EtOAc and HCl. The phases were separated and theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with saturated NaHCO₃ solution, water and brine, dried over MgSO₄and evaporated. The crude intermediate (9.5 g; 106%) was used for thenext step without further purification.

Intermediate 5 tert-Butyl2-(1-(4-chlorophenyl)cyclobutyl)-3-oxopiperidine-1-carboxylate

A mixture of intermediate 4 (10.5 g; 40 mmol), diisopropyl ethylamine(1.2 eq; 8 ml) and Boc₂O (1.1 eq; 9 g) in acetonitrile was stirred at65° C. for 5 h. The cooled mixture was diluted with EtOAc and washedwith HCl, water and brine, dried over MgSO₄ and evaporated. The residuewas purified by silica gel column chromatography to give the product(8.8 g; 61%) as colorless oil.

ESI-MS [M+Na³⁰]=386 Calculated for C₂₂H₂₅ClNaNO₃=386

Intermediate 6 (E)-tert-Butyl2-(1-(4-chlorophenyl)cyclobutyl)-4-((dimethylamino)methylene)-3-oxopiperidine-1-carboxylate

A mixture of intermediate 5 (3.24 g; 8.9 mmol) and Bredereck's reagent(1.25 eq; 2.3 ml; 11 mmol) in toluene (90 ml) was stirred at 120° C. inthe micro wave. The mixture was diluted with EtOAc and was washed withwater and brine, dried over MgSO₄ and evaporated. The residue waspurified by silica gel column chromatography using EtOAc/heptane (1/1)to give the product (2.95 g; 79%) as pale yellow foam.

ESI-MS [M+H⁺]=419 Calculated for C₂₃H₃₁ClN₂O₃=418

Intermediate 78-(1-(4-Chlorophenyl)cyclobutyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinehydrochloride

7.1 Step A

Intermediate 6 (100 mg; 0.275 mmol) and formadine acetate (86 mg; 3 eq)were dissolved in toluene and heated at 100° C. until completeconversation. The mixture was concentrated and the residue was dissolvedin EtOAc and H₂O. The organic layer was washed with saturated NaHCO₃solution, brine, dried over MgSO₄ and concentrated. The residue waspurified by PTLC to give the product (32 mg; 29%) as colorless oil.

7.2 Step B

The product of step A was dissolved in 5 N isopropanolic hydrochloricacid (1 ml) and stirred for 2 h at room temperature. The solvents wereevaporated and the product was dried in vacuo.

ESI-MS [M+H⁺]=300 Calculated for C₁₇H₁₈ClN₃=299

Intermediate 8 tert-Butyl7-(1-(4-chlorophenyl)cyclobutyl)-1-(2-hydroxyethyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate

A mixture of intermediate 6 (0.78 g; 2.15 mmol) and 2-hydrazinylethanol(1.25 eq; 0.2 g) in ethanol (2.5 ml) was stirred at 80° C. for 1 h.Ethanol was evaporated under reduced pressure and the residue waspartitioned between EtOAc and water. The organic layer was washed withwater, saturated NaHCO₃ solution and brine, dried over MgSO₄ andevaporated. The residue was purified by silica gel column chromatography(EtOAc/heptane (2/1) to EtOAc) to give a mixture of regioisomericproducts as colourless oils. Yield (165 mg; 17%)

ESI-MS [M+H⁺]=432 Calculated for C₂₃H₃₀ClN₃O₃=431

Intermediate 9 tert-Butyl7-(1-(4-chlorophenyl)cyclobutyl)-2-(2-hydroxyethyl)-4,5-dihydro-2H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate

The more polar product of the above reaction was identified astert-butyl7-(1-(4-chlorophenyl)cyclobutyl)-2-(2-hydroxyethyl)-4,5-dihydro-2H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate.Yield (401 mg; 43%)

ESI-MS [M+H⁺]=432 Calculated for C₂₃H₃₀ClN₃O₃=431

Intermediate 10 tert-butyl1-(2-aminoethyl)-7-(1-(4-chlorophenyl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate

10.1 Step A

The intermediate 8 (165 mg; 0.38 mmol) was dissolved in dichloromethaneand treaded with triethylamine (0.08 ml; 1.5 eq) and mesylchloride (0.04ml; 1.25) at 0° C. for 2 h. The mixture was diluted with dichloromethaneand washed with dilute HCl, saturated NaHCO₃ solution, brine, dried overMgSO₄ and evaporated. The crude product was used without furtherpurification for the next step.

10.2 Step B

A solution of the product of the step A and NaN₃ (0.04 g; 1.5 eq) in DMF(1 ml) was stirred for 90 min at 85° C. The mixture was diluted withEtOAc and washed with water, brine, dried over MgSO₄ and evaporated. Thecrude product was used without further purification for the next step.

10.3 Step C

A solution of the product of the step B and PPh₃ (150 mg; 1.5 eq) inTHF/water (1 ml; 20/1) was stirred at 65° C. for 2 h. The mixture wascooled to room temperature and diluted with EtOAc. The organic layer waswashed with water, brine, dried over MgSO₄ and evaporated. The residuewas purified by silica gel column chromatography (DCM=>DCM/MeOH 10/1)give the product (0.98 g) as colourless oils.

ESI-MS [M+H⁺]=431 Calculated for C₂₃H₃₁ClN₄O₂=430

Intermediate 11 tert-Butyl2-(2-aminoethyl)-7-(1-(4-chlorophenyl)cyclobutyl)-4,5-dihydro-2H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate

The compound was prepared analogously to intermediate 10 from tert-butyl7-(1-(4-chlorophenyl)cyclobutyl)-2-(2-hydroxyethyl)-4,5-dihydro-2H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate(intermediate 9).

ESI-MS [M+H⁺]=431 Calculated for C₂₃H₃₁ClN₄O₂=430

Intermediate 12 Ethyl8-(1-(4-chlorophenyl)cyclobutyl)-2-methyl-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylatedihydrochloride

12.1 Step A

A mixture of intermediate 6 (200 mg; 0.48 mmol), ethylacetoacetate (0.07ml; 1.1 eq; 0.525 mmol) and ammonium acetate (300 mg; 8 eq) in aceticacid (5 ml) was stirred at 100° C. for 1 h. The mixture was cooled toroom temperature and diluted with ethyl acetate. The mixture was washedwith water (2×), saturated NaHCO₃ solution, brine and dried overanhydrous MgSO₄ and concentrated. The residue was purified by silica gelcolumn chromatography to give the product (123 mg; 53%) as colorlessoil.

12.2 Step B

The product of the step A (20.0 mg) was dissolved in 5N isopropanolichydrochloric acid (1 ml) and stirred for 2 h at room temperature. Thesolvents were evaporated and the product (16.9 mg; 97%) was dried invacuo.

ESI-MS [M+H⁺]=385 Calculated for C₂₂H₂₅ClN₂O₂=384

Intermediate 13 tert-Butyl2-(aminomethyl)-8-(1-(4-chlorophenyl)cyclobutyl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

A solution of intermediate 6 (0.5 g; 1.2 mmol), aminoacetamidinedibromide (0.35 g; 1.2 eq) and freshly prepared sodium ethoxide (0.14 gsodium; (5 eq) in 5 ml ethanol) in ethanol (5 ml) was stirred at 85° C.for 4 h. The solvent was removed under reduced pressure and the residuewas diluted with EtOAc and water. The layers were separated and theorganic layer was washed with water, brine, dried over MgSO₄ andevaporated. The residue was purified by silica gel column chromatographyto give the product (0.153 g; 30%) as brown oil.

ESI-MS [M+H⁺]=429 Calculated for C₁₈H₂₁ClN₄=428

Intermediate 14 tert-Butyl4-bromo-2-(1-(4-chlorophenyl)cyclobutyl)-3-oxopiperidine-1-carboxylate

Intermediate 9 (2 g, 1.0 eq) was dissolved in THF and pyridinium bromideperbromide (2.15 g, 1.1 eq) was added. The resulting mixture was stirredfor 2 h at room temperature until complete conversion. The reactionmixture was diluted with ethyl acetate and washed with saturated sodiumthiosulfite, water and brine. The organic layer was dried over

MgSO₄ and concentrated in vacuum. The residue was purified by silica gelcolumn chromatography to give the product (1.6 g, 66%) as a yellow oil.

ESI-MS [M+H⁺]=492 Calculated for C₂₄H₃₄ClN₅O₂S=491

Intermediate 15 tert-Butyl4-(1-(4-chlorophenyl)cyclobutyl)-2-(cyanomethyl)-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate

Intermediate 14 (500 mg, 1 eq) and 2-Cyanothioacetamide (136 mg, 1.2 eq)were dissolved in DMSO and heated to 65° C. for 5 h. The reactionmixture was dissolved with ethyl acetate and washed with water (3×) andbrine. The organic layer was dried over MgSO₄ and concentrated invacuum. The residue was purified by silica gel column chromatography togive the product (236 mg, 46%) as a yellow oil.

ESI-MS [M+H⁺]=492 Calculated for C₂₄H₃₄ClN₅O₂S=491

Intermediate 16 tert-Butyl2-(2-aminoethyl)-4-(1-(4-chlorophenyl)cyclobutyl)-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate

Raney-nickel (10 mg, 10 wt %) was added to a solution of intermediate 15(100 mg) in ethanol. The reaction mixture was stirred under hydrogenatmosphere over night at room temperature. The reaction mixture wasfiltered over a plug of celite, concentrated and used for the next stepwithout further purification.

ESI-MS [M+H⁺]=448 Calculated for C₂₃H₃₀ClN₃O₂S=447

Example 17-(1-Phenylcyclobutyl)-2-(2-(propylsulfonamido)ethyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-6-iumchloride

ESI-MS [M+H⁺]=403 Calculated for C₂₁H₃₀ClN₄O₂S=402

Step A

The intermediate 11 was dissolved in dichloromethane. DMAP (1.5 eq) andn-propyl sulfonylchlorid were added. The reaction was stirred for 3hours at room temperature. After complete conversation the reaction wasdiluted with dichloromethane and washed with HCl (0.1 N), water andbrine, dried over MgSO₄ and evaporated. The residue was purified by PTLCto give the desired n-propyl sulfonylamid.

Step B

The product of the step above was dissolved in MeOH and Pd/C (10 wt %)and ammonia formate (25 eq) were added. The resulting reaction mixturewas stirred over night at room temperature. The reaction mixture wasfiltered, diluted with EtOAc and washed with water (3×). The organiclayer was dried over MgSO₄, evaporated and used directly for the nextstep.

Step C

The product of the step above was treated with HCl in isopropanol (5 N).After stirring for 2 hours at room temperature the reaction wascomplete. The solvents were evaporated and the product was dried invacuo.

Example 2N-(Azetidin-3-yl)-N-(2-(7-(1-(4-chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)propane-1-sulfonamidedihydrochloride

N-(Azetidin-3-yl)-N-(2-(7-(1-(4-chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)propane-1-sulfonamidedihydrochloride was prepared according to the procedure of example 10using 1-Boc-3-iodo-azetidine.

ESI-MS [M+H⁺]=492 Calculated for C₂₄H₃₄ClN₅O₂S=491

Example 38-(1-(4-Chlorophenyl)cyclobutyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2-carbonitrilehydrochloride

Step A

A solution of intermediate 6 (100 mg; 0.24 mmol), 2-methyl2-thiopseudourea sulfate (86 mg; 1.3 eq; 0.312 mmol) and sodium ethoxide(freshly prepared; 1.5 eq) in ethanol (1 ml) was stirred at 90° C. for 4h. The solvent was removed under reduced pressure and the residue wasdiluted with EtOAc and water. The layers were separated and the organiclayer was washed with water, brine, dried over MgSO₄ and evaporated. Theresidue was purified by silica gel column chromatography to give theproduct (63 mg; 59%) as colorless oil.

Step B

To a stirred and cooled (0° C.) solution of the product (50 mg; 0.112mmol) of the step A in dichloromethane (1 ml) was added m-CPBA (77 mg; 4eq) and the mixture was stirred at the same temperature for 2 h. Themixture was diluted with dichloromethane and washed with 10% aqueousNa₂SO₃, saturated NaHCO₃ solution, brine, dried over MgSO₄ andevaporated. The residue was purified by PTLC using EtOAc/heptane (3/2)to give the product (25 mg; 47%) as colorless oil.

Step C

A mixture of the product (50 mg; 0.105 mmol) of the step B and NaCN (8mg; 1.5 eq) in DMF (1 ml) was stirred at 110° C. for 90 min. The mixturewas diluted with EtOAc and washed with water, brine dried over MgSO₄ andevaporated. The residue was purified by PTLC to give the product (18 mg;40%) as colorless oil.

Step D

The product of the step C was diluted in dichloromethane and anhydrous 3N HCl in dioxane was added. The mixture was stirred for 30 min at roomtemperature. The mixture was diluted with EtOAc and washed withsaturated NaHCO₃ solution, brine dried and evaporated. The residue waspurified by PTLC to give the product as colorless oil.

ESI-MS [M+H⁺]=325 Calculated for C₂₂H₂₅ClN₂O₂=324

Example 4(8-(1-(4-Chlorophenyl)cyclobutyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)methanaminedihydrochloride

Intermediate 13 was dissolved in 5 N isopropanolic hydrochloric acid (1ml) and stirred for 2 h at room temperature. The solvents wereevaporated and the product was dried in vacuo.

ESI-MS [M+H⁺]=329 Calculated for C₁₈H₂₁ClN₄=328

Example 52-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)ethanaminedihydrochloride

The intermediate 10 was dissolved in 5 N isopropanolic hydrochloric acid(1 ml) and stirred for 2 h at room temperature. The solvents wereevaporated and the product was dried in vacuo.

ESI-MS [M+H⁺]=431 Calculated for C₁₈H₂₃ClN₄=430

Example 62-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethanaminedihydrochloride

The intermediate 11 was dissolved in 5 N isopropanolic hydrochloric acid(1 ml) and stirred for 2 h at room temperature. The solvents wereevaporated and the product was dried in vacuo.

ESI-MS [M+H⁺]=331 Calculated for C₁₈H₂₃ClN₄=330

Example 7 General Procedure

Step A

The intermediate 10 was dissolved in dichloromethane. DMAP (1.5 eq) andthe appropriate sulfonylchlorid were added. The reaction was stirred for3 hours at room temperature. After complete conversation the reactionwas diluted with dichloromethane and washed with HCl (0.1 N), water andbrine, dried over MgSO₄ and evaporated. The residue was purified by PTLCto give the desired sulfonylamid.

Step B

The product of the step A was treated with HCl in isopropanol (5 N).After stirring for 2 hours at room temperature the reaction wascomplete. The solvents were evaporated and the product was dried invacuo.

Example 7.1N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)ethyl)propane-1-sulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)ethyl)propane-1-sulfonamidehydrochloride was prepared according to the general procedure of example7 using propane-1-sulfonyl chloride.

ESI-MS [M+H⁺]=437 Calculated for C₂₁H₂₉ClN₄O₂S=436

Example 7.2N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)ethyl)-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-ylethyl)-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride was prepared according to the general procedure of example7 using 1-methyl-1H-pyrazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=475 Calculated for C₂₂H₂₇ClN₆O₂S=474

Example 7.3N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)ethyl)-3-fluoropropane-1-sulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)ethyl)-3-fluoropropane-1-sulfonamidehydrochloride was prepared according to the general procedure of example7 using 3-fluoropropane-1-sulfonyl chloride.

ESI-MS [M+H⁺]=455 Calculated for C₂₁H₂₈ClFN₄O₂S=455

Example 7.4N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride was prepared according to the general procedure of example7 using 1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=475 Calculated for C₂₂H₂₇ClN₆O₂S=474

Example 8 General Procedure

Step A

Intermediate 13 was dissolved in dichloromethane. DMAP (1.5 eq) andsulfonylchlorid were added. The reaction was stirred for 3 hours at roomtemperature. After complete conversation the reaction was diluted withdichloromethane and washed with HCl (0.1 N), water and brine, dried overMgSO₄ and evaporated. The residue was purified by PTLC to give thedesired sulfonylamid.

Step B

The product of the step A was treated with HCl in isopropanol (5 N).After stirring for 2 hours at room temperature the reaction wascomplete. The solvents were evaporated and the product was dried invacuo.

Example 8.1N-((8-(1-(4-Chlorophenyl)cyclobutyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)methyl)propane-1-sulfonamidehydrochloride

N-((8-(1-(4-Chlorophenyl)cyclobutyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)methyl)propane-1-sulfonamidehydrochloride was prepared according to the general procedure of example8 using propane-1-sulfonyl chloride.

ESI-MS [M+H⁺]=435 Calculated for C₂₁H₂₇ClN₄O₂S=434

Example 8.2N-((8-(1-(4-Chlorophenyl)cyclobutyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)methyl)-1-cyclopropylmethanesulfonamidehydrochloride

N-((8-(1-(4-Chlorophenyl)cyclobutyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)methyl)-1-cyclopropylmethanesulfonamidehydrochloride was prepared according to the general procedure of example8 using 1-cyclopropylmethanesulfonyl chloride.

ESI-MS [M+H⁺]=447 Calculated for C₂₂H₂₅ClN₄O₂S=446

Example 8.3N-((8-(1-(4-Chlorophenyl)cyclobutyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride

N-((8-(1-(4-Chlorophenyl)cyclobutyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride was prepared according to the general procedure of example8 using 1-methyl-1H-pyrazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=473 Calculated for C₂₂H₂₅ClN₆O₂S=472

Example 8.4N-((8-(1-(4-Chlorophenyl)cyclobutyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

N-((8-(1-(4-Chlorophenyl)cyclobutyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride was prepared according to the general procedure of example8 using 1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=473 Calculated for C₂₂H₂₅ClN₆O₂S=472

Example 8.5N-((8-(1-(4-Chlorophenyl)cyclobutyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)methyl)-3-fluoropropane-1-sulfonamidehydrochloride

N-((8-(1-(4-Chlorophenyl)cyclobutyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)methyl)-3-fluoropropane-1-sulfonamidehydrochloride was prepared according to the general procedure of example8 using 3-fluoropropane-1-sulfonyl chloride.

ESI-MS [M+H⁺]=453 Calculated for C₂₁H₂₆ClN₄O₂S=452

Example 9 General Procedure

Step A

The intermediate 11 was dissolved in dichloromethane. DMAP (1.5 eq) andsulfonylchlorid were added. The reaction was stirred for 3 hours at roomtemperature. After complete conversation the reaction was diluted withdichloromethane and washed with HCl (0.1 N), water and brine, dried overMgSO₄ and evaporated. The residue was purified by PTLC to give thedesired sulfonylamid.

Step B

The product of the step A was treated with HCl in isopropanol (5 N).After stirring for 2 hours at room temperature the reaction wascomplete. The solvents were evaporated and the product was dried invacuo.

Example 9.1N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)propane-1-sulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)propane-1-sulfonamidehydrochloride was prepared according to the general procedure of example9 using propane-1-sulfonyl chloride.

ESI-MS [M+H⁺]=437 Calculated for C₂₁H₂₉ClN₄O₂S=436

Example 9.2N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)ethanesulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)ethanesulfonamidehydrochloride was prepared according to the general procedure of example9 using ethanesulfonyl chloride.

ESI-MS [M+H⁺]=423 Calculated for C₂₀H₂₇ClN₄O₂S=422

Example 9.3N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)methanesulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)methanesulfonamidehydrochloride was prepared according to the general procedure of example9 using methanesulfonyl chloride.

ESI-MS [M+H⁺]=409 Calculated for C₁₉H₂₅ClN₄O₂S=408

Example 9.4N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)benzenesulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)benzenesulfonamidehydrochloride was prepared according to the general procedure of example9 using benzenesulfonyl chloride.

ESI-MS [M+H⁺]=471 Calculated for C₂₄H₂₇ClN₄O₂S=470

Example 9.5N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-ethyl)butane-1-sulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)butane-1-sulfonamidehydrochloride was prepared according to the general procedure of example9 using butane-1-sulfonyl chloride.

ESI-MS [M+H⁺]=451 Calculated for C₂₂H₃₁ClN₄O₂S=450

Example 9.6N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-ethyl)-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride was prepared according to the general procedure of example9 using 1-methyl-1H-pyrazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=475 Calculated for C₂₂H₂₇ClN₆O₂S=474

Example 9.7N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride was prepared according to the general procedure of example9 using 1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=475 Calculated for C₂₂H₂₇ClN₆O₂S=474

Example 9.8N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)-3-fluoropropane-1-sulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)-3-fluoropropane-1-sulfonamidehydrochloride was prepared according to the general procedure of example9 using 3-fluoropropane-1-sulfonyl chloride.

ESI-MS [M+H⁺]=455 Calculated for C₂₁H₂₈ClN₄O₂S=454

Example 9.9N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-ethyl)cyclobutanesulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-ethyl)cyclobutanesulfonamidehydrochloride was prepared according to the general procedure of example9 using cyclobutanesulfonyl chloride.

ESI-MS [M+H⁺]=449 Calculated for C₂₂H₂₉ClN₄O₂S=448

Example 9.10N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-ethyl)-1-cyclopropylmethanesulfonamidehydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)-1-cyclopropylmethanesulfonamidehydrochloride was prepared according to the general procedure of example9 using 1-cyclopropylmethanesulfonyl chloride.

ESI-MS [M+H⁺]=449 Calculated for C₂₂H₂₃ClN₄O₂S=448

Example 9.11

N-(2-(7-(1-(4-chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)-2-methylpropane-1-sulfonamidehydrochloride was prepared according to the general procedure of example9 using 2-methylpropane-1-sulfonyl chloride.

ESI-MS [M+H⁺]=451 Calculated for C₂₂H₃₁ClN₄O₂S=450

Example 9.12N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)pyridine-3-sulfonamidedihydrochloride

N-(2-(7-(1-(4-Chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)pyridine-3-sulfonamidedihydrochloride was prepared according to the general procedure ofexample 9 using pyridine-3-sulfonyl chloride.

ESI-MS [M+H⁺]=472 Calculated for C₂₃H₂₆ClN₅O₂S=471

Example 10N-(2-(7-(1-(4-chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)ethyl)-N-methylpropane-1-sulfonamidehydrochloride

Step A

A mixture of the product of example 9.1, step A, methyl iodide and CsCO₃in acetonitrile was heated for 2 hours at 100° C. in the micro wave. Themixture was diluted with EtOAc and washed with water and brine, driedover MgSO₄ and evaporated. The residue was purified by PTLC to yield thedesired product.

Step B

The product of the step A was treated with HCl in isopropanol (5 N).After stirring for 2 hours at room temperature the reaction wascomplete. The solvents were evaporated and the product was dried invacuo.

ESI-MS [M+H⁺]=451 Calculated for C₂₂H₃₁ClN₄O₂S=450

Example 11N-(2-{1-[1-(4-Chlorophenyl)cyclobutyl]-1,2,3,4-tetrahydro-9H-b-carbolin-9-yl}ethyl)propane-1-sulfonamide11.1 1-[1-(4-Chlorophenyl)cyclobutyl]-2,3,4,9-tetrahydro-1H-b-carboline

1-(4-Chlorophenyl)cyclobutanecarbaldehyde (30 mg, 0.154 mmol) and2-(1H-indol-3-yl)ethanamine (27.7 mg, 0.17 mmol) were dissolved indichloromethane (3 mL). Trifluoroacetic acid (88 mg, 0.771 mmol) wereadded at 0° C. and the reaction mixture was stirred at room temperatureover night. The 5% NaHCO₃ solution was added. The aqueous layer wasextracted with dichloromethane. The combined organic layers were washedsuccessively with 5% NaHCO₃ solution and saturated sodium chloridesolution, dried (MgSO₄) and concentrated in vacuo. Yield: 36 mg (oil,0.107 mmol, 69%).

ESI-MS [M+H⁺]=337 Calculated for C₂₁H₂₁ClN₂=336.

11.2 tert-Butyl1-[1-(4-chlorophenyl)cyclobutyl]-1,3,4,9-tetrahydro-2H-b-carboline-2-carboxylate

1-[1-(4-Chlorophenyl)cyclobutyl]-2,3,4,9-tetrahydro-1H-b-carboline (2.5g, 7.42 mmol) were dissolved in tetrahydrofuran (30 mL). Triethylamine(2.253 g, 22.26 mmol) was added followed by di-tert-butyl dicarbonate(1.944 g, 8.91 mmol). The reaction mixture was stirred at roomtemperature over night. The solvent was evaporated in vacuo.Di-chloromethane (50 mL) was added and the organic layer washedsuccessively with saturated ammonium chloride solution (2×40 mL) andwater (40 mL). The organic phase was dried (MgSO₄) and concentrated invacuo. The crude product was used for the next step without furtherpurification. Yield: 3.1 g (beige solid, 96%).

ESI-MS [M+H⁺]=437 Calculated for C₂₆H₂₉ClN₂O₂=436.

11.3 tert-Butyl1-[1-(4-chlorophenyl)cyclobutyl]-9-(cyanomethyl)-1,3,4,9-tetrahydro-2H-b-carboline-2-carboxylate

60% Sodium hydride suspension in mineral oil (0.412 g, 10.3 mmol) in drydimethylformamide (25 mL) was stirred at room temperature under anatmosphere of nitrogen. tert-Butyl1-[1-(4-chlorophenyl)cyclobutyl]-1,3,4,9-tetrahydro-2H-b-carboline-2-carboxylate(3.0 g, 6.87 mmol) was added in small portions. After 30 min stirring atroom temperature 2-bromoacetonitrile (1.235 g, 10.3 mmol) indimethylformamide (5 mL) was added dropwise. The reaction mixture wasstirred at room temperature for two days. Water was added (1 mL). Thereaction mixture was concentrated in vacuo, dichloromethane (100 mL) wasadded and the organic solution successively washed with water (50 mL),saturated NaHCO₃ solution (30 mL) and water (30 mL). The organic layerwas dried (MgSO₄) and concentrated in vacuo. The crude product waspurified by flash chromatography (silica, dichloromethane). Yield: 2.7 g(83%).

ESI-MS [M+-isobutene+H⁺]=420 Calculated for C₂₈H₃₀ClN₃O₂=475.

11.4 tert-Butyl9-(2-aminoethyl)-1-[1-(4-chlorophenyl)cyclobutyl]-1,3,4,9-tetrahydro-2H-b-carboline-2-carboxylate

Lithium aluminium hydride (0.281 g, 7.41 mmol) was suspended in diethylether (40 mL). The slurry was cooled to −5° C. and tert-butyl1-[1-(4-chlorophenyl)cyclobutyl]-9-(cyanomethyl)-1,3,4,9-tetrahydro-2H-b-carboline-2-carboxylate(2.35 g, 4.94 mmol) was added in small portions. After stirring at −5°C. for 1 h 2N sodium hydroxide solution (15 mL) was added dropwise.After 10 min additional 2N sodium hydroxide solution (60 mL) was added.The aqueous layer was extracted with ethyl acetate (3×40 mL). Thecombined organic layers were washed with water (30 mL), dried (MgSO₄)and concentrated in vacuo. The crude product was purified by flashchromatography (silica, dichloromethane, methanol). Yield: 0.16 g (7%).

ESI-MS [M+H⁺]=480 Calculated for C₂₈H₃₄ClN₃O₂=479.

11.5N-(2-{1-[1-(4-chlorophenyl)cyclobutyl]-1,2,3,4-tetrahydro-9H-b-carbolin-9-yl}ethyl)propane-1-sulfonamide

tert-Butyl9-(2-aminoethyl)-1-[1-(4-chlorophenyl)cyclobutyl]-1,3,4,9-tetrahydro-2H-b-carboline-2-carboxylate(90 mg, 0.187 mmol) was dissolved in pyridine (2 mL). Triethylamine (38mg, 0.375 mmol) followed by propane-1-sulfonyl chloride (40 mg, 0.280mmol) were added. The reaction mixture was stirred over night. Thesolvent was evaporated in vacuo. The residue was treated withdichloromethane (10 mL) and washed successively with saturated ammoniumchloride solution (2×10 mL) and water (10 mL). The organic layer wasdried (MgSO₄) and concentrated in vacuo. The crude intermediate waspurified by flash chromatography (silica, dichloromethane, methanol).The obtained compound (58 mg, 0.099 mmol) was dissolved indichloromethane (2 mL) and excess 5M isopropanolic hydrochloric acid wasadded. The reaction mixture was stirred over night at room temperature.The solvent was evaporated in vacuo. Yield: 35 mg (0.067 mmol, 68%).

ESI-MS [M+H⁺]=486 Calculated for C₂₆H₃₂ClN₃O₂S=485.

Example 12N-(2-(4-(1-(4-chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-ylethyl)propane-1-sulfonamidehydrochloride

Step A

The crude intermediate 16 (30 mg) was dissolved in dichloromethane. DMAP(14 mg, 1.5 eq) and sulfonylchlorid (7 μl, 1.1 eq) were added. Thereaction was stirred for 3 hours at room temperature. After completeconversation the reaction was diluted with dichloromethane and washedwith HCl (0.1 N), water and brine, dried over MgSO₄ and evaporated. Theresidue was purified by PTLC to give the desired sulfonylamid.

Step B

The product of the step above was treated with HCl in isopropanol (1 ml,5 N). After stirring for 2 hours at room temperature the reaction wascomplete. The solvents were evaporated and the product (2.1 mg, 6% over2 steps) was dried in vacuo.

ESI-MS [M+H⁺]=454 Calculated for C₂₁H₂₈ClN₃O₂S₂=455

Example 13N-(2-(4-(1-(4-chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)ethyl)-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride

N-(2-(4-(1-(4-chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)ethyl)-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride was prepared analogously to example 12 using1-methyl-1H-pyrazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=492 Calculated for C₂₂H₂₆ClN₅O₂S₂=491

Example 14N-(2-(4-(1-(4-chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

N-(2-(4-(1-(4-chlorophenyl)cyclobutyl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride was prepared analogously to example 12 using1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=492 Calculated for C₂₂H₂₆ClN₅O₂S₂=491

Example 15

General Procedure

Step A

Preparation of 5-pyrrolidin-1-yl-3,4-dihydro-2H-pyridine-1-carboxylicacid tert-butyl

To a stirred solution of 3-oxo-piperidine-1-carboxylic acid tert-butylester (50, 0.25 mol) in anhydrous toluene (500 mL) was added pyrrolidine(26.6 g, 0.375 mol) in a round bottom flask filled with a Dean-Starktrap. After refluxing for 4 hrs, the mixture was concentrated underreduced pressure to give an orange oil, which was used directly in nextstep.

Step B

Preparation of 2-benzyl-3-oxo-piperidine-1-carboxylic acid tert-butylester

To a solution of crude5-pyrrolidin-1-yl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butylester (0.25 mol) in anhydrous CH₃CN (500 mL) was added benzyl bromide(33 mL, 0.275 mol) at 25° C. After refluxing for 16 hrs, the mixture wasconcentrated under reduced pressure, and then diluted with water,extracted with EtOAc (3×200 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄, concentrated and further purified bycolumn chromatography on silica gel (PE:EtOAc=15:1˜8:1) to afford2-benzyl-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (42 g,yield 58%, 2 steps) as a white solid.

Step C

Preparation of 2-benzyl-4-bromo-3-oxo-piperidine-1-carboxylic acidtert-butyl ester

To a solution of 2-benzyl-3-oxo-piperidine-1-carboxylic acid tert-butylester (25.9 g, 0.09 mol) in CHCl₃ (200 mL) was added Br₂ (15.8 g, 0.099mol, dissolved into 80 mL of CHCl₃) dropwise at 0° C. After theaddition, the mixture was stirred at 25° C. for 2 hrs, and then it wasfiltered. The filtrate was washed with saturated NaHSO₃ and brine, driedover Na₂SO₄ and concentrated under reduced pressure to afford crude2-benzyl-4-bromo-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (18g) as brown oil, which was used directly in the next step.

Step D

Preparation of4-benzyl-2-ethyl-6,7-dihydro-4H-thiazolo[4,5-c]pyridine-5-carboxylicacid tert-butyl esters

To a solution of 2-benzyl-3-oxo-piperidine-1-carboxylic acid tert-butylester in EtOH was added thioamide 40 A or 40 B at 25° C. After refluxingfor 2 hrs, TLC indicated the completed conversion of starting material.The mixture was concentrated under reduced pressure to give a residue,which was used directly in next step.

Step E

The protecting group was removed following standard protocol using acatalytic amount palladium and an excess of triethyl silane in thepresence of triethyl amine in dichloro methane at room temperatureyielding the desired product 42 A or 42 B in 84% yield.

Step F

1 Equivalent of amine 42 A or 42 B was dissolved in CH₂Cl₂ and to this,2 equivalents of DIEA in CH₂Cl₂ was added followed by 1 equivalent ofsulfonyl chloride in CH₂Cl₂. The reaction was shaken at room temperatureuntil completion. Any unreacted sulfonayl chloride can be scavenged byusing a Si-amine cartridge (from SiliCycle). The reaction was dried downand the crude product was purified by RP-HPLC.

The product of the step above was treated with HCl in isopropanol (1 ml,5 N). After stirring for 2 hours at room temperature the reaction wascomplete. The solvents were evaporated and the product was dried invacuo.

The following compounds were obtained or can be obtained using theprocedure described above.

Example 16

Further compounds of the invention which were obtained or can beobtained using the procedures disclosed herein include the following:

Biological Testing

1. [³H]-Glycine uptake into recombinant CHO cells expressing humanGlyT1: Human GlyT1c expressing recombinant hGlyT1c_(—)5_CHO cells wereplated at 20,000 cells per well in 96 well Cytostar-T scintillationmicroplates (Amersham Biosciences) and cultured to sub-confluency for 24h. For glycine uptake assays the culture medium was aspirated and thecells were washed once with 100 μl HBSS (Gibco BRL, #14025-050) with 5mM L-Alanine (Merck #1007). 80 μl HBSS buffer were added, followed by 10μl inhibitor or vehicle (10% DMSO) and 10 μl [³H]-glycine (TRK71,Amersham Biosciences) to a final concentration of 200 nM for initiationof glycine uptake. The plates were placed in a Wallac Microbeta(PerkinElmer) and continuously counted by solid phase scintillationspectrometry during up to 3 hours. Nonspecific uptake was determined inthe presence of 10 μM Org24598. IC₅₀ calculations were made byfour-parametric logistic nonlinear regression analysis (GraphPad Prism)using determinations within the range of linear increase of [³H]-glycineincorporation between 60 and 120 min.

2. Radioligand binding assays using recombinant CHO cell membranesexpressing human GlyT1:

Radioligand binding to human GlyT1c transporter-expressing membranes wascarried out as described in Mezler et al., Molecular Pharmacology74:1705-1715, 2008.

The following results were obtained with the compounds disclosed in theexamples:

Example radioligand binding K ^(iapp) [μmol] 6 ≧10 7.1 ≦1 7.2 ≦10 7.3 ≦17.4 ≦1 8.1 ≦1 8.2 ≦1 8.3 ≦1 8.4 ≦1 8.5 ≦1 9.1 ≦1 9.2 ≦10 9.3 ≦1 9.4 ≦19.5 ≦1 9.6 ≦1 9.7 ≦1 9.8 ≦1 9.9 ≦1 9.10 ≦1 9.11 ≦1 9.12 ≦1 10 ≦1 11 ≦1

1. A heterocyclic compound of the formula (I)

wherein A is a 5- or 6-membered heterocyclic ring; R isR¹—W-A¹-Q-Y-A²-X¹—; R¹ is hydrogen, C₁-C₆-alkyl,C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl, halogenated C₁-C₆-alkyl,hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₁-C₆-alkylcarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkyl, (optionally substitutedC₆-C₁₂-aryl-C₁-C₆-alkyl)amino-C₁-C₄-alkyl, optionally substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl, optionally substitutedC₃-C₁₂-heterocyclyl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl, C₁-C₆-alkylcarbonyl,C₁-C₆-alkoxycarbonyl, halogenated C₁-C₆-alkoxycarbonyl,C₆-C₁₂-aryloxycarbonyl, aminocarbonyl, C₁-C₆-alkylaminocarbonyl,(halogenated C₁-C₄-alkyl)aminocarbonyl, C₆-C₁₂-arylaminocarbonyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionally substituted C₆-C₁₂-aryl,hydroxy, C₁-C₆-alkoxy, halogenated C₁-C₆-alkoxy, C₁-C₆-hydroxyalkoxy,C₁-C₆-alkoxy-C₁-C₄-alkoxy, amino-C₁-C₄-alkoxy,C₁-C₆-alkylamino-C₁-C₄-alkoxy, di-C₁-C₆-alkylamino-C₁-C₄-alkoxy,C₁-C₆-alkylcarbonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylcarbonylamino-C₁-C₄-alkoxy,C₁-C₆-alkoxycarbonylamino-C₁-C₄-alkoxy, C₆-C₁₂-aryl-C₁-C₄-alkoxy,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkoxy, (halogenatedC₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylsulfonylamino-C₁-C₄-alkoxy,(C₆-C₁₂-aryl-C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclylsulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclyl-C₁-C₄-alkoxy, C₆-C₁₂-aryloxy,C₃-C₁₂-heterocyclyloxy, C₁-C₆-alkylthio, halogenated C₁-C₆-alkylthio,C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino, di-C₁-C₆-alkylamino,di-(halogenated C₁-C₆-alkyl)amino, C₁-C₆-alkylcarbonylamino,(halogenated C₁-C₆-alkyl)carbonylamino, C₆-C₁₂-arylcarbonylamino,C₁-C₆-alkylsulfonylamino, (halogenated C₁-C₆-alkyl)sulfonylamino,C₆-C₁₂-arylsulfonylamino or optionally substituted C₃-C₁₂-heterocyclyl;W is —NR⁸— or a bond; A¹ is optionally substituted C₁-C₄-alkylene or abond; Q is —S(O)₂—, —C(O)— or a bond; Y is —NR⁹— or a bond; A² isoptionally substituted C₁-C₄-alkylene, C₁-C₄-alkylene-CO—,—CO—C₁-C₄-alkylene, C₁-C₄-alkylene-O—C₁-C₄-alkylene,C₁-C₄-alkylene-NR¹⁰—C₁-C₄-alkylene, optionally substitutedC₂-C₄-alkenylen, optionally substituted C₂-C₄-alkynylene, optionallysubstituted C₆-C₁₂-arylene, optionally substituted C₆-C₁₂-heteroaryleneor a bond; X¹ is —O—, —NR¹¹, —S—, optionally substituted C₁-C₄-alkylene,optionally substituted C₂-C₄-alkenylen, optionally substitutedC₂-C₄-alkynylene or a bond, with the proviso that if Q is a bond, W is—NR⁸— or Y is —NR⁹—; R² is hydrogen, halogen, C₁-C₆-alkyl, halogenatedC₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, —CN, C₂-C₆-alkenyl, C₂-C₆-alkynyl,optionally substituted C₆-C₁₂-aryl, hydroxy, C₁-C₆-alkoxy, halogenatedC₁-C₆-alkoxy, C₁-C₆-alkoxycarbonyl, C₂-C₆-alkenyloxy,C₆-C₁₂-aryl-C₁-C₄-alkoxy, C₁-C₆-alkylcarbonyloxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, aminosulfonyl, amino,C₁-C₆-alkylamino, C₂-C₆-alkenylamino, nitro or optionally substitutedC₃-C₁₂-heterocyclyl, or two radicals R² together with the ring atoms ofA to which they are bound form an optionally substituted 5- or6-membered ring; R³ is hydrogen, halogen, C₁-C₆-alkyl or C₁-C₆-alkoxy,or two radicals R³ together with the carbon atom to which they areattached form a carbonyl group; R⁴ is hydrogen, C₁-C₆-alkyl, halogenatedC₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,amino-C₁-C₄-alkyl, CH₂CN, —CHO, C₁-C₄-alkylcarbonyl, (halogenatedC₁-C₄-alkyl)carbonyl, C₁-C₄-alkoxycarbonyl, C₆-C₁₂-arylcarbonyl,C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl, —C(═NH)NH₂, —C(═NH)NHCN,C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, amino or C₃-C₁₂-heterocyclyl;X² is —O—, —NR⁶—, —S—, >CR^(12a)R^(12b) or a bond; X³ is —O—, —NR⁷—,—S—, >CR^(13a)R^(13b) or a bond; R⁵ is optionally substitutedC₆-C₁₂-aryl, optionally substituted C₃-C₁₂-cycloalkyl or optionallysubstituted C₃-C₁₂-heterocyclyl; n is 0, 1, 2; R⁶ is hydrogen orC₁-C₆-alkyl; R⁷ is hydrogen or C₁-C₆-alkyl; R⁸ is hydrogen orC₁-C₆-alkyl; R⁹ is hydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl,amino-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl-C₁-C₄-alkyl orC₃-C₁₂-heterocyclyl; or R⁹, R¹ together are C₁-C₄-alkylene; or R⁹ isC₁-C₄-alkylene that is bound to a carbon atom in A² and A² isC₁-C₄-alkylene or to a carbon atom in X¹ and X¹ is C₁-C₄-alkylene; R¹⁰is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkylsulfonyl; R¹¹ is hydrogen orC₁-C₆-alkyl, or R⁹, R¹¹ together are C₁-C₄-alkylene, R^(12a) ishydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy; R^(12b) is hydrogen or C₁-C₆-alkyl, or R^(12a), R^(12b)together are carbonyl or optionally substituted C₁-C₄-alkylene, whereinone —CH₂— of C₁-C₄-alkylene may be replaced by an oxygen atom or —NR¹⁴—;R^(13a) is hydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy; R^(13b) is hydrogen or C₁-C₆-alkyl, or R^(13a), R^(13b)together are carbonyl or optionally substituted C₁-C₄-alkylene, whereinone —CH₂— of C₁-C₄-alkylene may be replaced by an oxygen atom or —NR¹⁵—;R¹⁴ is hydrogen or C₁-C₆-alkyl; R¹⁵ is hydrogen or C₁-C₆-alkyl; and or aphysiologically tolerated salt thereof.
 2. The compound orphysiologically tolerated salt thereof of claim 1, wherein A is a ringselected from the group consisting of the following 5- or 6-memberedheterocyclic rings:


3. The compound or physiologically tolerated salt thereof of claim 1,wherein —Y-A²-X¹— comprises at least 2, 3 or 4 atoms in the main chain.4. The compound or physiologically tolerated salt thereof of claim 1,wherein R¹ is hydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl,halogenated C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl, C₆-C₁₂-aryl-C₁-C₄-alkyl,C₃-C₁₂-cycloalkyl, C₂-C₆-alkenyl, optionally substituted C₆-C₁₂-aryl,hydroxy, C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino,di-C₁-C₆-alkylamino or optionally substituted C₃-C₁₂-heterocyclyl. 5.(canceled)
 6. The compound or physiologically tolerated salt thereof ofclaim 1, wherein A¹ is a bond, or A¹ is C₁-C₄-alkylene and W is —NR⁸—.7. (canceled)
 8. The compound or physiologically tolerated salt thereofof claim 1, wherein A² is optionally substituted C₁-C₄-alkylene, or A²is C₆-C₁₂-arylene selected from the group consisting of phen-1,4-yleneand phen-1,3-ylene, or C₆-C₁₂-heteroarylene selected from the groupconsisting of pyrid-2,5-ylene and pyrid-2,4-ylene.
 9. (canceled) 10.(canceled)
 11. The compound or physiologically tolerated salt thereof ofclaim 1, wherein X¹ is —O— or NR¹¹, or X¹ is optionally substitutedC₁-C₄-alkylene and A² is a bond, or X¹ is a bond.
 12. (canceled)
 13. Thecompound or physiologically tolerated salt thereof of claim 12, wherein—Y-A²-X¹— is —NR⁹—C₁-C₄-alkylene-.
 14. The compound or physiologicallytolerated salt thereof of claim 1, wherein R¹—W-A¹-Q-Y-A²-X¹— isR¹S(O)₂—NH-A²-X¹—, R¹—NH—S(O)₂-A²-X¹—, R¹—C(O)—NH-A²-X¹—,R¹—NH—C(O)-A²-X¹— or R¹—NH-A²-X¹.
 15. The compound or physiologicallytolerated salt thereof of claim 1, having one of the formulae

wherein R¹, W, A¹, Q, Y, A², X¹, R², R³, R⁴, X², X³, R⁵, n are asdefined in claim
 1. 16.-18. (canceled)
 19. The compound orphysiologically tolerated salt thereof of claim 1, wherein R⁴ ishydrogen, C₁-C₆-alkyl, halogenated C₁-C₄-alkyl, amino-C₁-C₄-alkyl,CH₂CN, C₁-C₄-alkylcarbonyl, (halogenated C₁-C₄-alkyl)carbonyl,C₁-C₄-alkoxycarbonyl, —C(═NH)NH₂, —C(═NH)NHCN, C₁-C₆-alkylsulfonyl,amino or C₃-C₁₂-heterocyclyl.
 20. The compound or physiologicallytolerated salt thereof of claim 1, wherein X² is >CR^(12a)R^(12b), andX³ is a bond.
 21. (canceled)
 22. The compound or physiologicallytolerated salt thereof of claim 1, wherein R^(12a) is hydrogen andR^(12b) is hydrogen, or R^(12a) is C₁-C₆-alkyl and R^(12b) is hydrogenor C₁-C₆-alkyl, or R^(12a), R^(12b) together are optionally substitutedC₁-C₄-alkylene such as optionally substituted 1,3-propylene. 23.-25.(canceled)
 26. The compound or physiologically tolerated salt thereof ofclaim 1, wherein R⁵ is optionally substituted aryl.
 27. The compound orphysiologically tolerated salt thereof of claim 26, having the formula

wherein A, R, R², R³, R⁴, X², X³, n are as defined in claim 1; andR^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f) independently arehydrogen, halogen, optionally substituted C₁-C₆-alkyl, halogenatedC₁-C₆-alkyl, CN, hydroxy, C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino or C₃-C₁₂-heterocyclyl.
 28. The compound orphysiologically tolerated salt thereof of claim 27, wherein R⁹ ishydrogen.
 29. The compound or physiologically tolerated salt thereof ofclaim 28, wherein n is
 1. 30. (canceled)
 31. The compound orphysiologically tolerated salt thereof of claim 1, wherein A is a ringselected from the group consisting of the following 5- or 6-memberedheterocyclic rings:

R is R¹—W-A¹-Q-Y-A²-X¹—; R¹ is hydrogen, C₁-C₆-alkyl,C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl, halogenated C₁-C₆-alkyl,C₁-C₁₂-cycloalkyl, optionally substituted C₆-C₁₂-aryl, or optionallysubstituted C₃-C₁₂-heterocyclyl; W is a bond; A¹ is a bond; Q is—S(O)₂—, —C(O)— or a bond; Y is —NR⁹— or a bond; with the proviso thatif Q is a bond, Y is —NR⁹—; A² is C₁-C₄-alkylene; X¹ is a bond; R² ishydrogen; R³ is hydrogen; R⁴ is hydrogen or C₁-C₄-alkoxycarbonyl; X² is>CR^(12a)R^(12b); X³ is a bond; R⁵ is optionally substituted phenyl; R⁹is hydrogen or C₃-C₁₂-heterocyclyl; and R^(12a) is hydrogen; R^(12b) ishydrogen, or R^(12a), R^(12b) together are optionally substitutedC₁-C₄-alkylene.
 32. (canceled)
 33. A pharmaceutical compositioncomprising a carrier and the compound of claim
 1. 34. (canceled) 35.(canceled)
 36. A method for treating a neurologic or psychiatricdisorder or pain in a mammalian patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecompound or physiologically tolerated salt thereof of claim 1, whereinthe neurologic or psychiatric disorder is selected from the groupconsisting of: glycinergic neurotransmission dysfunction, glutamatergicneurotransmission dysfunction, dementia, cognitive impairment, attentiondeficit disorder, hyperactivity, anxiety disorder, a mood disorder suchas depression, a bipolar disorder, schizophrenia, and a psychoticdisorder. 37.-42. (canceled)